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Programming of adult blood pressure by maternal protein restriction: Role of nephrogenesis
Abstract
Modest maternal protein restriction leads to hypertension and a reduced number of glomeruli in adult male but not female offspring. This study determined whether a more severe protein restriction has equivalent effects on male and female rat offspring, and examined the role of nephrogenesis in this programming.
Sprague-Dawley rats were fed a protein-restricted (5% protein) diet throughout (LLP), or during the first (LLP/NP) or second (NP/LLP) half of pregnancy. Controls ate a normal diet (NP, 19% protein). Adult offspring were chronically instrumented at 22 weeks; glomerular number and volume were estimated using stereologic techniques.
Mean arterial pressures in male offspring were significantly higher in LLP (136 +/- 2 mm Hg) or NP/LLP (137 +/- 2 mm Hg) than in LLP/NP (125 +/- 1 mm Hg) or NP (125 +/- 2 mm Hg). Moreover, the hypertension was salt-sensitive (increase of 16 +/- 4 mm Hg in LLP on a high Na(+) diet compared to 2 +/- 2 mm Hg in NP). Glomerular number (per kidney) was reduced (15,400 +/- 2,411 in LLP vs. 27,208 +/- 1,534 in NP) but average individual glomerular volume was not different (1.98 +/- 0.18 106 micro(3) in LLP vs. 2.01 +/- 0.14 106 micro(3) in NP). Female offspring showed qualitatively similar results.
Severe maternal dietary protein restriction reduces glomerular number and programs for salt-sensitive adult hypertension in both female and male offspring. The window of sensitivity of adult blood pressure to prenatal protein restriction falls within the period of nephrogenesis in the rat. These data are consistent with the hypothesis that maternal protein restriction causes adult hypertension in the offspring through impairment of renal development.
... Table 1 indicates maternal malnutrition is the most common factor related to kidney disease and hypertension of developmental origins. A variety of nutritional insults can cause renal programming, including high sucrose consumption [51], high-fructose diet [52,53], protein restriction [58][59][60][61][62][63], calorie restriction [64], high-fat diet [65,66], high-salt diet [67], and low-salt intake [68]. Second, maternal illness is also interfering with renal programming. ...
... The most common adverse renal outcome of renal programming being studied is hypertension [51][52][53][54][55][56][57][58][59][60][61][62][63][64][65]. Albuminuria was demonstrated in offspring born of dams with protein restriction [58], diabetes [72], or hypoxia [78]. ...
... Albuminuria was demonstrated in offspring born of dams with protein restriction [58], diabetes [72], or hypoxia [78]. The glomerular filtration rate (GFR), an index of renal function, was reported as decreased [66,76], unaltered [54,55,59,60], or even increased [58] in different models of renal programming. Additionally, reduced nephron number [57,76,78,79], renal hypertrophy [71], glomerular hypertrophy [78], and tubulointerstitial injury [66,78] are major morphological deficits being reported. ...
The renin-angiotensin-aldosterone system (RAAS) is implicated in hypertension and kidney disease. The developing kidney can be programmed by various early-life insults by so-called renal programming, resulting in hypertension and kidney disease in adulthood. This theory is known as developmental origins of health and disease (DOHaD). Conversely, early RAAS-based interventions could reverse program processes to prevent a disease from occurring by so-called reprogramming. In the current review, we mainly summarize (1) the current knowledge on the RAAS implicated in renal programming; (2) current evidence supporting the connections between the aberrant RAAS and other mechanisms behind renal programming, such as oxidative stress, nitric oxide deficiency, epigenetic regulation, and gut microbiota dysbiosis; and (3) an overview of how RAAS-based reprogramming interventions may prevent hypertension and kidney disease of developmental origins. To accelerate the transition of RAAS-based interventions for prevention of hypertension and kidney disease, an extended comprehension of the RAAS implicated in renal programming is needed, as well as a greater focus on further clinical translation.
... All data extracted from the 65 studies are provided in Additional file 1. Of these studies, 29 used Wistar rats (23 performed protein restriction and 6 performed food restriction [43][44][45][46][47][48]), 21 used Sprague-Dawley rats (7 protein restriction [49][50][51][52][53][54][55] and 14 food restriction [56][57][58][59][60][61][62][63][64][65][66][67][68][69]), 3 used other strains of rats (2 protein restriction with Wistar-Kyoto [70,71] and 1 food restriction with Long Evans [72]) and 12 used various strains of mice (7 protein restriction [73][74][75][76][77][78][79] and 5 food restriction [80][81][82][83][84]). We therefore focused primarily on studies of Wistar and Sprague-Dawley rats. ...
... Considering offspring of Wistar and Sprague-Dawley dams protein-restricted for the duration of gestation (studies listed in Table 2; complete data provided in Additional file 1), birthweight was reduced in both sexes in one study [38], but in another was reduced in females but not males [42]. Conversely, weight at 3 weeks [54] and 7 weeks of age [30] was reduced in both sexes, whereas weight at 4 [22], 22, and 35 weeks [54] was reduced only in males. Blood pressure was generally increased in both sexes [20,26,30,34,54], although in one study, this was true at 6 months of age, but at 3 months, only males were affected [53]. ...
... Conversely, weight at 3 weeks [54] and 7 weeks of age [30] was reduced in both sexes, whereas weight at 4 [22], 22, and 35 weeks [54] was reduced only in males. Blood pressure was generally increased in both sexes [20,26,30,34,54], although in one study, this was true at 6 months of age, but at 3 months, only males were affected [53]. Heart rate was sometimes increased in both sexes [26], sometimes in females only [34]. ...
Background
Males and females may experience different effects of early-life adversity on life-long health. One hypothesis is that male foetuses invest more in foetal growth and relatively less in placental growth, and that this makes them susceptible to poor nutrition in utero, particularly if nutrition is reduced part-way through gestation.
Objectives
Our objectives were to examine whether (1) food and/ or protein restriction in rats and mice has consistent sex-dependent effects, (2) sex-dependency differs between types of outcomes, and (3) males are more severely affected when restriction starts part-way through gestation.
Data sources
PubMed and Web of Science were searched to identify eligible studies.
Study eligibility criteria
Eligible studies described controlled experiments that restricted protein or food during gestation in rats or mice, examined physiological traits in offspring from manipulated pregnancies, and tested whether effects differed between males and females.
Results
Our search identified 292 articles, of which the full texts of 72 were assessed, and 65 were included for further synthesis. A majority (50) used Wistar or Sprague-Dawley rats and so these were the primary focus. Among studies in which maternal diet was restricted for the duration of gestation, no type of trait was consistently more severely affected in one particular sex, although blood pressure was generally increased in both sexes. Meta-analysis found no difference between sexes in the effect of protein restriction throughout gestation on blood pressure. Among studies restricting food in the latter half of gestation only, there were again few consistent sex-dependent effects, although three studies found blood pressure was increased in males only. Meta-analysis found that food restriction in the second half of gestation increased adult blood pressure in both sexes, with a significantly greater effect in males. Birthweight was consistently reduced in both sexes, a result confirmed by meta-analysis.
Conclusions
We found little support for the hypotheses that males are more affected by food and protein restriction, or that effects are particularly severe if nutrition is reduced part-way through gestation. However, less than half of the studies tested for sex by maternal diet interactions to identify sex-dependent effects. As a result, many reported sex-specific effects may be false positives.
... As shown in Table 1, different types of suboptimal nutrition in pregnancy and/or lactation have been shown to be capable of inducing several phenotypes of renal programming in adult offspring, including elevation of BP, glomerular hypertrophy, glomerular and tubulointerstitial injury, changes of glomerular filtration rate (GFR), proteinuria, and altered renal transcriptome. Additionally, certain early-life nutritional insults can cause low nephron endowment, as in the case of maternal caloric restriction [25,26], maternal protein restriction [34,36], iron deficiency [54], and multideficient diet [60]. However, nephron endowment can also be unaltered [37,50], or even increased in response to maternal imbalanced nutrition-induced renal programming [62]. ...
... A reduction of nephron number, in the presence of compensatory hypertrophy, would be expected to counteract a decreased GFR. Interestingly, variations of GFR observed in different models of renal programming can be unaltered [25,30,36,37], reduced [46,61], or even increased [34,60,62]. These data indicate that there is a different level of compensation in the setting of a low nephron endowment in response to various nutritional insults. ...
... Rat models of low protein feeding have been extensively used to study the mechanisms of nutritional programming [65]. In rodents, offspring exposed to protein restriction ranging from 6%-9% during pregnancy and/or lactation period develop hypertension [33][34][35][36][37][38][39][40][41]. It appears that a large scale of early-life protein restriction shows a higher propensity to induce hypertension earlier, even in childhood [38]. ...
Kidney disease and hypertension both have attained the status of a global pandemic. Altered renal programming resulting in kidney disease and hypertension can begin in utero. Maternal suboptimal nutrition and oxidative stress have important implications in renal programming, while specific antioxidant nutrient supplementations may serve as reprogramming strategies to prevent kidney disease and hypertension of developmental origins. This review aims to summarize current knowledge on the interplay of maternal nutrition and oxidative stress in response to early-life insults and its impact on developmental programming of kidney disease and hypertension, covering two aspects. Firstly, we present the evidence from animal models supporting the implication of oxidative stress on adult kidney disease and hypertension programmed by suboptimal maternal nutrition. In the second part, we document data on specific antioxidant nutrients as reprogramming strategies to protect adult offspring against kidney disease and hypertension from developmental origins. Research into the prevention of kidney disease and hypertension that begin early in life will have profound implications for future health.
... Taking into account that higher cortisol concentrations are found in adults who had low birth weight, it can be assumed that fetal nephrogenesis also plays a role in potentially high blood pressure values (considering that babies with low birth weight have fewer nephrons at birth) with lifelong effects on renal function and cardiovascular control. A study that dealt with this in more detail was conducted on rats and showed that the offspring of mothers who had low-protein diet during pregnancy could have higher blood pressure due to impaired maternalno-fetalna interakcija i moduliranje u stvaranju nove populacije: pregled postojećih dokaza o povezanosti fetalne ishrane i razvoja hroničnih bolesti u toku života maternofetal interaction and modulation in creating a new population: a review of current evidence on the relationship between fetal nutrition and the development of chronic diseases later in life genezi [9]. Još jedna studija koja ide u prilog tome jeste ona koju su sproveli Lengli-Evans i saradnici, a koja implicira da sled događaja od glukortikoidnog dejstva u fetusu do hipertenzije kod odraslih obuhvata razvoj preosetljivosti na glukokortikoide odraslih, sa aktivacijom sistema renin-angiotenzin i povećanom osetljivošću krvnih sudova na angiotenzin II, a sve sa osvrtom na pothranjenost majke [10]. ...
... Pretpostavlja se da tokom neonatalnog perioda kortizol ograničava proteolizu IGF vezujućeg proteina 3 (IGFBP3) i da samim tim smanjuje bioraspoloživost IGF-a [14]. Niski nivoi IGF-1 primećeni su i kod dece koja su rođena kao mala fetal nephrogenesis [9]. Another study that supports this finding is the one conducted by Langley-Evans and colleagues which implies that the sequence of events from glucocorticoid action in the fetus to hypertension in adulthood includes the development of sensitivity to glucocorticoids in adults, with the activation of the renin-angiotensin system and increased sensitivity of blood vessels to angiotensin II, all with reference to maternal malnutrition [10]. ...
The concept of fetal programming has found its place in science and keeps lighting the way to better understanding of fetal life and its impact on postnatal and adult life. Its capacity is much wider than a common recognition of the fact that different disorders in pregnancy impact fetal health, and these capacities keep being confirmed by various observational studies and experimental models. Another fact that makes fetal programming even harder to confirm and accept is the long period between the stimulus and its consequences, as well as various factors that can change and influence this period of one's lifetime. Nevertheless, different hypotheses are present, concerning suboptimal fetal health and nutrition and their contribution to the development of chronic diseases during one's lifetime - inadequate nutrition during intrauterine period and early childhood can permanently change one's physiology and metabolism, which contributes to a possible development of chronic diseases (hypertension, coronary artery disease, stroke, diabetes, etc.). The aim of this paper is to review current evidence on the relationship between fetal nutrition and the risk of chronic diseases later in life. A detailed review of current literature and the analysis of various studies aimed at following neonates to their adulthood in order to determine the significance of fetal programming. An association between suboptimal fetal growth and a higher risk of metabolic syndrome, insulin resistance, diabetes type 2, and hypertension, has been proven by the studies conducted within different populations and age groups. Based on the evidence presented in this paper, it can be concluded that fetal programming has been recognized as significant and is on the way to becoming the third contributing factor in the development of chronic diseases during one's lifetime, along with a genetic predisposition and lifestyle.
... Nous avons donc considéré que les souriceaux issus de ce groupe d'étude avaient été exposés aux glucocorticoïdes uniquement en postnatal via la lactation, de J0 à J7. De façon intéressante, nous ne retrouvons dans ce groupe d'étude complémentaire, ni l'activation transcriptionelle intense des gènes cibles des voies corticostéroïdes néonatale, ni le phénotype de programmation foetale du GR et de la 11bHSD2 (données non montrées), pointant la fin de la gestation comme une fenêtre développementale importante pour le rein et la mise en place de la signalisation corticostéroïde dans cet organe, comme cela avait été suggéré par d'autres auteurs (Lori L. Woods, Weeks, et Rasch 2004;Wyrwoll, Mark, et Waddell 2007a). ...
... L. Woods et al. 2001). De façon intéressante,Woods et al. ont montré qu'une exposition au cours de la deuxième partie de la gestation (du 11 ème jour à la mise bas), suffisait à induire le phénotype d'HTA, suggérant là encore une fenêtre de susceptibilité au cours de la phase de néphrogenèse active (Lori L.Woods, Weeks, et Rasch 2004). D'autres restrictions en macro-ou micronutriments pendant la gestation peuvent programmer la survenue d'une HTA dans la descendance, notamment l'induction d'une carence en fer(Lewis et al. 2002), un régime pauvre ou riche en sodium(Koleganova et al. 2011), un régime carencé en calcium(Bergel et Belizán 2002), en zinc (Tomat et al. 2010), en vitamine D (Tare et al. 2011) ou un régime riche ou pauvre en donneurs de groupement méthyl (Tain et al. 2018), sans entrainer de RCF significative de façon systématique. ...
La prématurité et la restriction de croissance fœtale (RCF) sont deux pathologies néonatales fréquentes, qui ont en commun des difficultés d'adaptation à la naissance, avec le développement d'une tubulopathie chez le prématuré, et le développement d'une hypertension artérielle (HTA) a l'âge adulte. L’objectif de ce travail était d’évaluer l'implication des voies de signalisation corticostéroïdes rénales dans la survenue de ces complications dans un modèle murin de prématurité induite par des lipopolysaccharides, et un modèle de RCF par exposition périnatale a la dexaméthasone. Dans ce travail nous avons montré que ces deux pathologies programment la survenue d’une HTA à l’âge adulte chez les mâles, associée à des altérations franches de la signalisation corticostéroïde rénale en période périnatale et une augmentation de la sensibilité rénale aux glucocorticoïdes à l’âge adulte. Dans le modèle de prématurité, nous avons identifié la transmission transgénérationelle d’anomalies de régulation de la pression artérielle chez les mâles jusqu’à la 3ème génération de souris, associée à une hypométhylation du promoteur de GILZ et une augmentation d’expression de GILZ. Notre étude a permis l’identification de potentiels mécanismes moléculaires impliqués dans la programmation fœtale de l’HTA, sur plusieurs générations, ce qui pourrait aboutir à une meilleure prise en charge des patients nés prématurés ou avec une RCF, et de leurs descendants.
... Diabetes in utero is associated with offspring salt-sensitive hypertension in rats [8]. Maternal dietary protein restriction is associated with fewer glomeruli and salt-sensitive hypertension in adult offspring [9]. Moreover, direct inhibitors of RAAS precipitate kidney injury and adult hypertension while certain drugs (e.g., non-steroidal anti-inflammatory drugs, NSAID) suppress RAAS activity and associate with renal developmental injury and adult hypertension [10,11]. ...
... Most data stem from rodent models. In the models of low dietary protein intake and postnatal unilateral nephrectomy in rats, the hypertension in adult life was salt-sensitive [9]. In the protein-restricted rat model, this was associated with altered apical sodium transport proteins in adult offspring kidney: increased NKCC-2, but not sodium chloride-cotransporter (NCC) or epithelial sodium channel (ENaC) [157] and increased NA-K-ATPase [158]. ...
Adverse events during fetal life such as insufficient protein intake or elevated transfer of glucocorticoid to the fetus may impact cardiovascular and metabolic health later in adult life and are associated with increased incidence of type 2 diabetes, ischemic heart disease and hypertension. Several adverse factors converge and suppress the fetal renin–angiotensin–aldosterone system (RAAS). The aim of this review is to summarize data on the significance of RAAS for kidney development and adult hypertension. Genetic inactivation of RAAS in rodents at any step from angiotensinogen to angiotensin II (ANGII) type 1 receptor (AT1) receptors or pharmacologic inhibition leads to complex developmental injury to the kidneys that has also been observed in human case reports. Deletion of the ‘protective’ arm of RAAS, angiotensin converting enzyme (ACE) 2 (ACE-2) and G-protein coupled receptor for Angiotensin 1–7 (Mas) receptor does not reproduce the AT1 phenotype. The changes comprise fewer glomeruli, thinner cortex, dilated tubules, thicker arterioles and arteries, lack of vascular bundles, papillary atrophy, shorter capillary length and volume in cortex and medulla. Altered activity of systemic and local regulators of fetal-perinatal RAAS such as vitamin D and cyclooxygenase (COX)/prostaglandins are associated with similar injuries. ANGII–AT1 interaction drives podocyte and epithelial cell formation of vascular growth factors, notably vascular endothelial growth factor (VEGF) and angiopoietins (Angpts), which support late stages of glomerular and cortical capillary growth and medullary vascular bundle formation and patterning. RAAS-induced injury is associated with lower glomerular filtration rate (GFR), lower renal plasma flow, kidney fibrosis, up-regulation of sodium transporters, impaired sodium excretion and salt-sensitive hypertension. The renal component and salt sensitivity of programmed hypertension may impact dietary counseling and choice of pharmacological intervention to treat hypertension.
... However, women with renal disease are at risk for adverse maternal and fetal outcomes (Harville et al., 2019;Suarez et al., 2019;Garovic et al., 2022); specifically, a history of recovered AKI in women who later get pregnant increases the risk for preeclampsia and small-for-gestationalage babies (Tangren et al., 2017;Piccoli et al., 2018;Tangren et al., 2018). The maternal kidney controls the systemic vascular tone and blood pressure through the renin-angiotensin system (RAS), primarily via the balance of vasoconstrictive angiotensin II (AngII) to vasodilating factors, which can also influence the localized placental RAS and fetal RAS driving nephrogenesis (Woods et al., 2001;Woods et al., 2004;Lumbers et al., 2019). In addition to the limited studies on maternal outcomes following recovered AKI, no studies have addressed offspring beyond the neonatal stage or the mechanisms of heritable and long-term disease (Perico et al., 2018). ...
Introduction: Acute kidney injury (AKI) is rapidly increasing in global incidence and a healthcare burden. Prior maternal AKI diagnosis correlates with later pregnancy complications. As pregnancy influences developmental programming, we hypothesized that recovered parental AKI results in poor pregnancy outcomes, impaired fetal growth, and adult offspring disease.
Methods: Using a well-characterized model of rhabdomyolysis-induced acute kidney injury (RIAKI), a form of AKI commonly observed in young people, we confirmed functional renal recovery by assessing glomerular filtration rate (GFR) 2 weeks following RIAKI. We bred sham and recovered RIAKI sires and dams in timed, matched matings for gestational day (GD) 16.5 and offspring (birth–12 weeks, 6 months) study.
Results: Despite a normal GFR pre-pregnancy, recovered RIAKI dams at GD16.5 had impaired renal function, resulting in reduced fetoplacental ratios and offspring survival. Pregnant RIAKI dams also had albuminuria and less renal megalin in the proximal tubule brush border than shams, with renal subcapsular fibrosis and higher diastolic blood pressure. Growth-restricted offspring had a reduced GFR as older adults, with evidence of metabolic inefficiency in male offspring; this correlated with reduced renal AngII levels in female offspring from recovered RIAKI pairings. However, the blood pressures of 6-month-old offspring were unaffected by parental RIAKI.
Conclusions: Our mouse model demonstrated a causal relationship among RIAKI, gestational risk, and developmental programming of the adult-onset offspring GFR and metabolic dysregulation despite parental recovery.
... It has been reported previously that during the first two weeks of pregnancy, the provision of a 5% protein diet only (undernutrition) led to a reduction in brain weight, size, and cortical thickness of the brain (Gressens et al., 1997). A severe gestational maternal protein restriction in rats caused a reduced number of glomeruli and hypertension in both male and female newborns, this hypertension is salt-sensitive and worsens with age, but is approximately equivalent in males and females (Woods et al., 2004) Chronic energy deficit or maternal undernutrition means having a body mass index (BMI) below 18.5. If the females are under-nourished females at the time of conception, then during pregnancy (when there are additional demands due to the growing fetus), they are unlikely to improve their nutritional status. ...
... In animals, offspring born to dams fed a protein restriction diet showed a significant reduction in the number of nephrons, coupled with hypertension and glomerular hypertrophy in adulthood [47,48]. In addition, renal apoptosis was found to be upregulated in newborn mice due to maternal food restriction during gestation [49], potentially contributing to the reduced nephron number. ...
The developmental programming hypothesis proposes that adverse environmental insults during critical developmental periods increase the risk of diseases later in life. The kidneys are deemed susceptible to such a process, although the exact mechanisms remain elusive. Many factors have been reported to contribute to the developmental origin of chronic kidney diseases (CKD), among which peri-gestational nutrition has a central role, affecting kidney development and metabolism. Physiologically, the link between malnutrition, reduced glomerular numbers, and increased blood pressure is key in the developmental programming of CKD. However, recent studies regarding oxidative stress, mitochondrial dysfunction, epigenetic modifications, and metabolic changes have revealed potential novel pathways for therapeutic intervention. This review will discuss the role of imbalanced nutrition in the development of CKD.
... Maternal protein restriction [38][39][40] and iron and vitamin A deficiency [41,42] have been identified as factors that can disrupt normal fetal nephrogenesis-the process of kidney development. Furthermore, a recent study revealed the significance of fetal programming in nephrogenesis by demonstrating the effects of maternal fasting for 16 h per day [43]. ...
The human intestinal microbiota is a highly intricate structure with a crucial role in promoting health and preventing disease. It consists of diverse microbial communities that inhabit the gut and contribute to essential functions such as food digestion, nutrient synthesis, and immune system development. The composition and function of the gut microbiota are influenced by a variety of factors, including diet, host genetics, and environmental features. In pediatric patients, the gut microbiota is particularly dynamic and vulnerable to disruption from endogenous and exogenous factors. Recent research has focused on understanding the interaction between the gut and kidneys. In individuals with chronic kidney disease, there is often a significant disturbance in the gut microbiota. This imbalance can be attributed to factors like increased levels of harmful toxins from the gut entering the bloodstream, inflammation, and oxidative stress. This review looks at what is known about the link between a child’s gut–kidney axis, how dysbiosis, or an imbalance in the microbiome, affects chronic kidney disease, and what treatments, both pharmaceutical and non-pharmaceutical, are available for this condition.
... Several models of congenitally reduced nephron number exist. One model uses restriction in maternal protein and calorie intake during gestation (20)(21)(22)(23), however this leads to generalized epigenetic responses and affects multiple organs in offspring (24)(25)(26)(27). Another model resembling premature kidneys involves cesarean delivery one to two days prior to natural birth in mice, and results in reduced nephron endowment with evidence of CKD manifested by albuminuria, hypertension, and lower GFR 5 weeks later. ...
Preterm birth results in low nephron endowment and increased risk of acute kidney injury (AKI) and chronic kidney disease (CKD). To understand the pathogenesis of AKI and CKD in preterm humans, we generated novel mouse models with a 30-70% reduction in nephron number by inhibiting or deleting Ret tyrosine kinase in the developing ureteric bud. These mice developed glomerular and tubular hypertrophy followed by the transition to CKD, recapitulating the renal pathological changes seen in humans born preterm. We injected neonatal mice with gentamicin, a ubiquitous nephrotoxic exposure in preterm infants, and detected more severe proximal tubular injury in mice with low nephron number compared to controls with normal nephron number. Mice with low nephron number have reduced proliferative repair with more rapid development of CKD. Furthermore, mice had more profound inflammation with highly elevated levels of MCP-1 and CXCL10, produced in part by damaged proximal tubules. Our study directly links low nephron endowment with postnatal renal hypertrophy, which in this model is maladaptive and results in CKD. Underdeveloped kidneys are more susceptible to gentamicin-induced AKI, suggesting that AKI in the setting of low nephron number is more severe and further increases the risk of CKD in this vulnerable population.
... In vivo studies have shown that early-life protein-restricted mice pups have a weak cardiovascular function, altered muscle fiber composition, and reduced exercise capacity in the adult stage [8]. Protein restriction in utero is associated with impaired structures and functions of several organs, including the liver, kidney, and pancreas [10][11][12][13]. Fetal protein malnutrition causes liver steatosis, disrupts nephrogenesis, and disturbs β-cell function and insulin secretion; therefore, leading to hyperlipidemia, hypertension, and glucose intolerance [14,15]. ...
Skeletal muscle is programmable, and early-life nutritional stimuli may form epigenetic memory in the skeletal muscle, thus impacting adult muscle function, aging, and longevity. In the present study, we designed a one-month protein restriction model using post-weaning rats, followed by a two-month rebound feeding, to investigate how early-life protein restriction affects overall body growth and muscle development and whether these influences could be corrected by rebound feeding. We observed comprehensive alterations immediately after protein restriction, including retarded growth, altered biochemical indices, and disturbed hormone secretion. Transcriptome profiling of the gastrocnemius muscle followed by gene ontology analyses revealed that “myogenic differentiation functions” were upregulated, while “protein catabolism” was downregulated as a compensatory mechanism, with enhanced endoplasmic reticulum stress and undesired apoptosis. Furthermore, methylome profiling of the gastrocnemius muscle showed that protein restriction altered the methylation of apoptotic and hormone secretion-related genes. Although most of the alterations were reversed after rebound feeding, 17 genes, most of which play roles during muscle development, remained altered at the transcriptional level. In summary, early-life protein restriction may undermine muscle function in the long term and affect skeletal muscle development at the both transcriptional and methylation levels, which may hazard future muscle health.
... The possible existence of signaling based on maternal nutritional state is supported by the finding that males have an enhanced catch-up growth in case of placental IUGR whilst such enhanced postnatal development is more evident in females in cases of maternal IUGR. These findings may be consistent with the fact that, in humans and mouse models, females show better survival than males in the face of malnutrition [37][38][39][40][41]. ...
Intrauterine growth restriction (IUGR) and later obesity and metabolic disorders have classically been associated with maternal malnutrition, but most cases of IUGR are related to placental insufficiency. The current study, using a swine model for IUGR and obesity, aimed to determine the interaction of birth weight (categorized as low birth weight [LBW] or normal birth-weight [NBW]) and postnatal diet (categorized as maintenance diet [MD] or fattening diet [FD]) on body weight, adiposity and metabolic traits. FD induced higher body weight and adiposity (both p < 0.0001), with higher fructosamine levels (p < 0.005) and a trend toward higher HOMA-β index (p = 0.05). NBW pigs remained heavier than LBW pigs during the early juvenile period (p < 0.005), but there were no differences at later stages. There were no differences in metabolic traits during juvenile development, but there were differences in adulthood, when LBW pigs showed higher glucose and lower insulin levels than NBW pigs (both p < 0.05). These results suggest that (a) FD allows LBW offspring to achieve similar obesity in adulthood as NBW offspring, and (b) glucose metabolism is more compromised in obese LBW than obese NBW pigs. The comparison of our data with previous studies highlights significant differences between offspring with LBW induced by maternal malnutrition or placental insufficiency, which should be considered when studying the condition.
... Early studies have suggested that a reduced filtration surface is one of the mechanisms underlying impaired renal salt handling associated with congenital or acquired nephron mass reduction, leading to salt-sensitive hypertension [87,88]. The appearance of salt intake-dependent proteinuria has been shown to increase in frequency with the progression of the CKD stage [89]. ...
Chronic kidney disease (CKD) is one of the strongest risk factors for hypertension, and hypertension can exacerbate the progression of CKD. Thus, the management of CKD and antihypertensive therapy are inextricably linked. Research over the past decades has shown that the human kidney is more diverse than initially thought. Subjects with low nephron endowment are at increased risk of developing CKD and hypertension, which is consistent with the theory of the developmental origins of health and disease. Combined with other lifetime risks of CKD, hypertension may lead to a vicious cycle consisting of podocyte injury, glomerulosclerosis and further loss of nephrons. Of note, recent studies have shown that the number of nephrons correlates well with the number of podocytes, suggesting that these two components are intrinsically linked and may influence each other. Both nephrons and podocytes have no or very limited regenerative capacity and are destined to decrease throughout life. Therefore, one of the best strategies to slow the progression of CKD is to maintain the "numbers" of these essential components necessary to preserve renal function. To this end, both the achievement of an optimal blood pressure and a maximum reduction in urinary protein excretion are essential. Lifestyle modifications and antihypertensive drug therapy must be carefully individualized to address the potential diversity of the kidneys.
... Much variation in preclinical studies is due to differences in study design, especially blood pressure measurement technique, and the specific species and genetic background of the animals [105][106][107]. The precise causes, timing, and severity of antenatal exposures remain nuanced and underappreciated aspects of hypertension programming [108,109]. Preclinical studies have not yet been able to parse out fully the relative contributions of specific exposures, their direct effects on placental and fetal structure and function, or the surrogate markers of such exposures such as low birth weight, preterm birth, and growth restriction. These issues mirror many of the same limitations observed in clinical and epidemiological data to date. ...
Purpose of Review
Synthesize the clinical, epidemiological, and preclinical evidence for antenatal programming of hypertension and critically appraise paradigms and paradoxes to improve translation.
Recent Findings
Clinical and epidemiological studies persistently demonstrate that antenatal factors contribute to programmed hypertension under the developmental origins of health and disease framework, including lower birth weight, preterm birth, and fetal growth restriction. Preclinical mechanisms include preeclampsia, maternal diabetes, maternal undernutrition, and antenatal corticosteroid exposure. However, clinical and epidemiological studies to date have largely failed to adequately identify, discuss, and mitigate many sources and types of bias in part due to heterogeneous study designs and incomplete adherence to scientific rigor. These limitations have led to incomplete and biased paradigms as well as persistent paradoxes that have significantly limited translation into clinical and population health interventions.
Summary
Improved understanding of these paradigms and paradoxes will allow us to substantially move the field forward.
... Many critical periods in development are present during the intrauterine period, infancy, childhood, and adolescence [2]. Alterations of the diet during gestation and lactation often result in low birth weight in o spring, which is related to a higher incidence of cardiometabolic and vascular diseases, including hypertension during adulthood [3][4][5][6]. A high sucrose diet before and during pregnancy and during lactation and the rst days after weaning resulted in a higher incidence of hypertension when the rat o spring reached adulthood [7]. ...
Cardiometabolic diseases, including hypertension, may result from exposure to high sugar diets during critical periods of development. Here, we studied the effect of sucrose ingestion during a critical period (CP) between postnatal days 12 and 28 of the rat on blood pressure, aortic histology, vascular smooth muscle phenotype, expression of metalloproteinases 2 and 9, and vascular contractility in adult rats and compared it with those of adult rats that received sucrose for 6 months and developed metabolic syndrome (MS). Blood pressure increased to a similar level in CP and MS rats. The diameter of lumen, media, and adventitia of aortas from CP rats was decreased. Muscle fibers were discontinuous. There was a decrease in the expression of alpha-actin in CP and MS rat aortas, suggesting a change to the secretory phenotype in vascular smooth muscle. Metalloproteinases 2 and 9 were decreased in CP and MS rats, suggesting that phenotype remains in an altered steady stationary state with little interchange of the vessel matrix. Aortic contraction to norepinephrine did not change, but aortic relaxation was diminished in CP and MS aortas. In conclusion, high sugar diets during the CP increase predisposition to hypertension in adults.
... Zambardo et al. have found that in the rat offspring of PR mothers, females after birth were lighter than males (15). Weight loss has also been reported in the adult rat offspring of PR mothers of both sexes (16), or in males only (14). Bellinger et al. have described that abdominal fat deposits increased only in rat males, but when it comes to gonadal fatfat content increased only in females (14). ...
The prenatal period, during which a fully formed newborn capable of surviving outside its mother’s body is built from a single cell, is critical for human development. It is also the time when the foetus is particularly vulnerable to environmental factors, which may modulate the course of its development. Both epidemiological and animal studies have shown that foetal programming of physiological systems may alter the growth and function of organs and lead to pathology in adulthood. Nutrition is a particularly important environmental factor for the pregnant mother as it affects the condition of offspring. Numerous studies have shown that an unbalanced maternal metabolic status (under- or overnutrition) may cause long-lasting physiological and behavioural alterations, resulting in metabolic disorders, such as obesity and type 2 diabetes (T2DM). Various diets are used in laboratory settings in order to induce maternal obesity and metabolic disorders, and to alter the offspring development. The most popular models are: high-fat, high-sugar, high-fat-high-sugar, and cafeteria diets. Maternal undernutrition models are also used, which results in metabolic problems in offspring. Similarly to animal data, human studies have shown the influence of mothers’ diets on the development of children. There is a strong link between the maternal diet and the birth weight, metabolic state, changes in the cardiovascular and central nervous system of the offspring. The mechanisms linking impaired foetal development and adult diseases remain under discussion. Epigenetic mechanisms are believed to play a major role in prenatal programming. Additionally, sexually dimorphic effects on offspring are observed. Therefore, further research on both sexes is necessary.
... The reduced critical mass of nephrons imposes immense workload on the individual nephrons by increasing hyperfiltration. Furthermore, glomerular sclerosis in adult life causes nephron death, thereby initiating a vicious cycle and thereby resulting in end stage renal disease (32). Moreover, obesity increases renal filtration load and the associated insulin resistance further augments the workload on the kidneys. ...
Early onset hypertension is one of many major medical disorders that have evolved over the current millennium across both the developing as well as the developed world. Though various mechanisms have been postulated for the evolution of hypertension in these individuals, one of the most relevant ones is that of low birth weight and its association with hypertension. Barker from historical evidence has postulated the foetal onset adult disease (FOAD) or Thrifty phenotype on Low Birth Weight (LBW) associated hypertension. Later, Brenner highlighted the importance of low nephron mass and future implications. In this review we elaborate the mechanisms that were postulated for LBW-related hypertension as well the potential antihypertensive therapy that may be used in these individuals.
... A possible explanation of our findings may be that kidney growth is more dependent on birth related variables in women than in men. However, a previous rat study found that female offspring were more resistant to protein restriction during pregnancy than male offspring 35 . ...
Background
Low birth weight (LBW) is associated with increased risk of kidney disease due to lower nephron endowment leading to hyperfiltration and subsequent nephron loss. Kidney size is commonly used as a proxy for nephron number. We compared kidney volume measured by magnetic resonance imaging (MRI) with measured glomerular filtration rate (mGFR) in adults with either normal or low birth weight.
Methods
Healthy individuals aged 42-52 years with LBW (1100-2300g) and normal birth weight (NBW; 3500-4000g) were invited. GFR was measured using plasma clearance of iohexol. Kidney volume was measured on MRI images using axial T2 images and coronal T1 images with fat saturation without contrast enhancement, calculations were performed according to the ellipsoid formula - π/6 x length x width x depth.
Results
We included 102 individuals (54 LBW, 48 NBW). Total kidney volume was 302 ± 51 ml for female NBW vs 258 ± 48 ml for female LBW (p=0.002). For men, total kidney volume was 347 ± 51 ml vs 340 ± 65 ml (p=0.7). mGFR was significantly associated with kidney volume with r=0.52 (p<0.001) for women and r=0.39 (p=0.007) for men. A mediation analysis showed that the association between birth weight and mGFR (significant in total sample and women) was mediated by kidney volume.
Conclusion
Healthy females born with LBW have smaller kidneys than healthy females born with NBW. The previously shown associations between LBW and lower mGFR in adult women might be explained by smaller kidney volume.
... A series of animal studies have suggested the importance of various environmental conditions in utero for total nephron counts [48][49][50][51][52][53]. These conditions include nutritional states, deficiencies of certain vitamins or minerals, and exposure to drugs or hazardous substances, all of which can inhibit nephrogenesis [54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69]. In addition, certain human gene variants have been shown to affect total nephron numbers [70,71]. ...
Total nephron counts vary widely between individuals and may affect susceptibility to certain diseases, including hypertension and chronic kidney disease. Detailed analyses of whole kidneys collected from autopsy patients remain the only method for accurately counting nephrons in humans, with no equivalent option in living subjects. Current technological advances have enabled estimations of nephron numbers in vivo, particularly the use of total nephron number and whole-kidney glomerular filtration rate to estimate the mean single-nephron glomerular filtration rate. The use of this method would allow physicians to detect dynamic changes in filtration function at the single-nephron level rather than to simply count the number of nephrons that appear to be functioning. Currently available methods for estimating total nephron number in clinical practice have the potential to overcome limitations associated with autopsy analyses and may therefore pave the way for new therapeutic interventions and improved clinical outcomes.
... 29 Fetal growth restriction (FGR) due to protein restriction in the diet also resulted in reduced number of nephrons and CKD in rats. 30 Full-term newborns usually have a complete number of nephrons. However, premature newborns may have a reduced number of nephrons due to FGR, impaired pregnancy, inadequate postnatal nutrition and treatment with medications, such as non-steroidal anti-inflammatory drugs after birth. ...
Prevention of kidney disease must begin before a woman becomes pregnant. For this prevention, it is necessary to act with doctors, health professionals, parents, schools and the community. This early prevention is important because the pathophysiology of chronic non-communicable diseases in adults would be related to events that occur during the prenatal period and in the first year of life. In an unfavorable intrauterine environment, the embryo/fetus undergoes adaptations resulting from epigenetics and intrinsic factors that could cause a renal maturation compromised. This is what we call fetal and perinatal programming of kidney diseases in adults. There are three types of prevention: the primary that aims to eliminate or reduce exposure to risk factors for chronic kidney disease, the secondary that eliminates or reduces exposure to risk factors and the tertiary that reduces or postpones long-term disease complications. However, the best and most effective prevention is the primary one with actions to control the future mother, the pregnant woman, the infant and older children until adolescence. The main primary prevention agents for kidney disease include the community, doctors and other health professionals, parents and caregivers, schools and day care centers. In this way, it will be possible to control the explosion of chronic kidney disease worldwide.
... A sex-specific impact of environmental factors on nephrogenesis has been suggested. Animal models show restriction of nutrients in the maternal diet during gestation reduce the nephron number in male, but not in female, offspring.37,38 It can also be possibly explained by endocrinological differences between men and women later in life. ...
We aimed to investigate whether month of birth is associated with blood pressure (BP) and prevalent hypertension in adults from a region with frost‐free days of <150 days and average temperatures − 13°C in winter, Xinjiang, China. We analyzed data for 6158 subjects from several surveys. We divided participants into April to August (n = 2624) and September to March (n = 3534) groups, based on length of maternal exposure to cold months, and analyzed BP, prevalent hypertension, and related factors. Diastolic BP in total subjects and systolic and diastolic BP in male subjects born between April and August were significantly higher than in those born between September and March. In sensitivity analysis, untreated males born between April and August showed significantly higher systolic and diastolic BP than did their counterparts. Subjects born between April and August showed significantly higher prevalence of hypertension (31.3% vs 27.8%, P = .003), and isolated systolic (23.3% vs 20.8%, P = .018) and diastolic hypertension (24.5% vs 21.4%, P = .004), than those born between September and March, which is similar for men. Birth between April and August showed 1.68 (95% CI: 1.06‐2.67, P = .027)‐fold increased odds for the prevalence of hypertension, independent of gender, age, body mass index, waist circumference, cigarette consumption, alcohol intake, and family history, compared with their counterparts. In conclusion, maternal exposure to cold spells during pregnancy may be associated with the increased risk of hypertension in offspring later in life, particularly among males, suggesting the involvement of maternal cold exposure during pregnancy in offspring hypertension development.
... . The number of nephrons in normal human kidneys is directly correlated with birth weight, with low birth weight a proxy marker of a sub-optimal intrauterine environment (Barnett et al., 2017;Hughson et al., 2008;Hughson, Farris 3rd, Douglas-Denton, Hoy, & Bertram, 2003;Lackland & Barker, 2009). Animal studies have shown that a maternal low protein (LP) diet, typically associated with low birth weight, results in offspring with 20-30% fewer nephrons than control kidneys (Boubred et al., 2016;Langley & Jackson, 1994;Langley-Evans, 1997;McMullen & Langley-Evans, 2005;Sahajpal & Ashton, 2003;Woods, Ingelfinger, Nyengaard, & Rasch, 2001;Woods, Weeks, & Rasch, 2004;Zimanyi et al., 2006). Although studies have established a reduction in nephron endowment in offspring of protein-restricted animals it is not clear whether these phenotypes are acquired during the early and/or late stages of kidney development. ...
A maternal low protein (LP) diet in rodents often results in low nephron endowment and renal pathophysiology in adult life, with outcomes often differing between male and female offspring. Precisely how a maternal LP diet results in low nephron endowment is unknown. We conducted morphological and molecular studies of branching morphogenesis and nephrogenesis to identify mechanisms and timepoints that might give rise to low nephron endowment. Sprague–Dawley rats were fed a normal protein (19.4% protein, NP) or LP (9% protein) diet for 3 weeks prior to mating and throughout gestation. Embryonic day 14.25 (E14.25) kidneys from males and females were either cultured for 2 days after which branching morphogenesis was quantified, or frozen for gene expression analysis. Real‐time PCR was used to quantify expression of key nephrogenesis and branching morphogenesis genes at E14.25 and 17.25. At E17.25, nephron number was determined in fixed tissue. There was no effect of either maternal diet or sex on branching morphogenesis. Nephron number at E17.25 was 14% lower in male and female LP offspring than in NP controls. At E14.25 expression levels of genes involved in branching morphogenesis (Gfrα1, Bmp4, Gdnf) and nephrogenesis (Hnf4a, Pax2, Wnt4) were similar in the dietary groups, but significant differences between sexes were identified. At E17.25, expression of Gfrα1, Gdnf, Bmp4, Pax2 and Six2 was lower in LP offspring than NP offspring, in both male and female offspring. These findings provide new insights into how a LP diet leads to low nephron endowment and renal sexual dimorphism.
... In our model, stress-induced increases in blood pressure did not persist. Other developmental programming models of adult onset hypertension have reported sustained hypertension rather than stress-dependent hypertension [29,30], but only in cases of severe maternal environmental insult (e.g., severe maternal diet protein restriction). A modest maternal protein restriction showed only male sex effects in rats [31] similar to our mouse model. ...
Fetal growth restriction (FGR) is associated with developmental programming of adult onset hypertension, which may be related to differences in nephron development. Prior studies showed that maternal nutrient restriction is associated with reduced nephrogenesis in rodents, especially in male progeny. We hypothesized that maternal genetic risk for FGR may similarly affect fetal kidney development, leading to adult onset hypertension. We employed an angiotensinogen (AGT) gene titration transgenic (TG) construct with 3 copies of the mouse AGT gene that mimics a common human genotype (AGT A[-6]G) associated with FGR. We investigated whether FGR in 2-copy (wild type, [WT]) progeny from 3-copy TG dams leads to developmental programming differences in kidney development and adult blood pressure compared with age- and sex-matched controls. Progeny were tested in the late fetal period (e17.5), neonatal period (2 weeks of age), and as young adults (12 weeks). We measured weights, tested for renal oxidative stress, compared renal DNA methylation profiles, counted the number of glomeruli, and measured adult blood pressure ± stress. Progeny from TG dams were growth restricted with evidence of renal oxidative stress, males showed fetal renal DNA hypermethylation, they had fewer glomeruli, and they developed stress-induced hypertension as adults. Their female siblings did not share this pathology and instead resembled progeny from WT dams. Surprisingly, glomerular counts in the neonatal period were not different between sexes or maternal genotypes. In turn, we suspect that differences in fetal renal DNA methylation may affect the long-term viability of glomeruli, rather than reducing nephrogenesis.
... Models of fetal hypertension programming have been done using relatively long-term alterations that included gestation and lactation that also resulted in low birth weight in offspring [79][80][81][82]. The decreased growth, in utero, might alter renal development causing hypertension. ...
Cardiovascular diseases are being included in the study of developmental origins of health and disease (DOHaD) and essential systemic hypertension has also been added to this field. Epigenetic modifications are one of the main mechanisms leading to early programming of disease. Different environmental factors occurring during critical windows in the early stages of life may leave epigenetic cues, which may be involved in the programming of hypertension when individuals reach adulthood. Such environmental factors include pre-term birth, low weight at birth, altered programming of different organs such as the blood vessels and the kidney, and living in disadvantageous conditions in the programming of hypertension. Mechanisms behind these factors that impact on the programming include undernutrition, oxidative stress, inflammation, emotional stress, and changes in the microbiota. These factors and their underlying causes acting at the vascular level will be discussed in this paper. We also explore the establishment of epigenetic cues that may lead to hypertension at the vascular level such as DNA methylation, histone modifications (methylation and acetylation), and the role of microRNAs in the endothelial cells and blood vessel smooth muscle which participate in hypertension. Since epigenetic changes are reversible, the knowledge of this type of markers could be useful in the field of prevention, diagnosis or epigenetic drugs as a therapeutic approach to hypertension.
... The rat models of low protein (LP) diet throughout pregnancy or bilateral ligation (LIG) of the uterine vessels during terminal pregnancy have been most widely used since they were designed to represent the most common causes of IUGR in humans, namely either malnutrition or placental insufficiency [5,[16][17][18][19][20]. Previous studies reported decreased nephron numbers and varying results concerning glomerular size, glomerular filtration rate, blood pressure, or proteinuria after both insults [18,[21][22][23]. An aggravated course of experimental glomerulonephritis was reported both after LP and LIG [19,24]. ...
This study was performed to identify transcriptional alterations in male intrauterine growth restricted (IUGR) rats during and at the end of nephrogenesis in order to generate hypotheses which molecular mechanisms contribute to adverse kidney programming. IUGR was induced by low protein (LP) diet throughout pregnancy, bilateral uterine vessel ligation (LIG), or intrauterine stress (IUS) by sham operation. Offspring of unimpaired dams served as controls. Significant acute kidney damage was ruled out by negative results for proteins indicative of ER-stress, autophagy, apoptosis, or infiltration with macrophages. Renal gene expression was examined by transcriptome microarrays, demonstrating 53 (LP, n = 12; LIG, n = 32; IUS, n = 9) and 134 (LP, n = 10; LIG, n = 41; IUS, n = 83) differentially expressed transcripts on postnatal days (PND) 1 and 7, respectively. Reduced Pilra (all IUGR groups, PND 7), Nupr1 (LP and LIG, PND 7), and Kap (LIG, PND 1) as well as increased Ccl20, S100a8/a9 (LIG, PND 1), Ifna4, and Ltb4r2 (IUS, PND 7) indicated that inflammation-related molecular dysregulation could be a “common” feature after IUGR of different origins. Network analyses of transcripts and predicted upstream regulators hinted at proinflammatory adaptions mainly in LIG (arachidonic acid-binding, neutrophil aggregation, toll-like-receptor, NF-kappa B, and TNF signaling) and dysregulation of AMPK and PPAR signaling in LP pups. The latter may increase susceptibility towards obesity-associated kidney damage. Western blots of the most prominent predicted upstream regulators confirmed significant dysregulation of RICTOR in LP (PND 7) and LIG pups (PND 1), suggesting that mTOR-related processes could further modulate kidney programming in these groups of IUGR pups.
Key messages
• Inflammation-related transcripts are dysregulated in neonatal IUGR rat kidneys.
• Upstream analyses indicate renal metabolic dysregulation after low protein diet.
• RICTOR is dysregulated after low protein diet and uterine vessel ligation.
... Animal studies have shown that a reduction in nephron endowment may result from maternal insults at specific times during development, with the early period of kidney development being extremely susceptible (Moritz & Bertram, 2006). These prenatal insults have included maternal exposure to glucocorticoids (Wintour et al., 2003), maternal calorie or protein restriction (Hoppe et al., 2007;Woods, Weeks, & Rasch, 2004) and uteroplacental insufficiency (Schreuder, Nyengaard, Fodor, van Wijk, & Delemarre-van de Waal, 2005;Wlodek et al., 2007). In the present study, we aimed to determine the effects of low to moderate alcohol exposure throughout pregnancy on nephron endowment and adult kidney function. ...
Alcohol during pregnancy can impair fetal development and result in offspring with neurodevelopmental deficits. Less is known about how low to moderate alcohol exposure can affect other organs, such as the kidney. Here, the effects of moderate ethanol exposure throughout pregnancy on kidney development were examined using a rat model. Rats were fed a liquid diet containing 6% ethanol (vol/vol) or control (0% ethanol) throughout pregnancy. Kidneys were collected at embryonic day (E) 20 or postnatal day (PN) 30 and total glomerular (nephron) number determined using unbiased stereology. Kidney function was examined in offspring at 8 and 19 months. At E20, fetuses exposed to ethanol had fewer nephrons with increased apoptosis. Alcohol exposure caused kidney dysregulation of pro‐ (Bax) and anti‐ (Bcl‐2) apoptotic factors, and reduced expression of the cell proliferation marker, Ki67. Prenatal alcohol decreased expression of Gdnf and Tgfb1, important regulators of branching morphogenesis, in male fetuses. At PN30, kidney volume and nephron number were lower in offspring exposed to prenatal alcohol. Urine flow and osmolality were normal in offspring exposed to alcohol however sodium excretion tended to be lower in females prenatally exposed to alcohol. Findings suggest exposure to moderate levels of alcohol during pregnancy results in impaired kidney development and leads to a permanent nephron deficit. Although the impact on adult kidney function was relatively minor, these data highlight that even at moderate levels, alcohol consumption during pregnancy can have deleterious long‐term outcomes and should be avoided.
... In fact, there is currently no animal model which fully reproduces the findings in human IUGR due to placental insufficiency in its entirety. In experimental investigations, IUGR has been induced through maternal malnutrition and low protein diet (Resnick, Morgane, Hasson, & Miller, 1982;Woods, Weeks, & Rasch, 2004), maternal iron deficiency (Gambling et al., 2002), hypoxic pregnancies (Bae et al., 2003;Botting et al., 2018Botting et al., , 2014Li et al., 2003;Mortola et al., 1990;Tong et al., 2011;Xu et al., 2006), surgical ablation/ uterine vessel ligation (Morrison et al., 2008;Turner & Trudinger, 2009), and occlusion of the umbilical artery through direct ligation (Wadley et al., 2013) or embolization (Bubb et al., 2009). Unfortunately, models that perhaps better simulate the pathophysiology of placental insufficiency including surgical removal of portions of the uterus or umbilical placental embolization typically involve use of large animals such as sheep that are expensive and not as easily studied for the longer-term impact of intrauterine exposures. ...
Aim:
We sought to explore whether fetal hypoxia exposure, an insult of placental insufficiency, is associated with left ventricular dysfunction and increased aortic stiffness at early postnatal ages.
Methods:
Pregnant Sprague Dawley rats were exposed to hypoxic conditions (11.5% FiO2 ) from embryonic day E15-21 or normoxic conditions (controls). After delivery, left ventricular function and aortic pulse wave velocity (measure of aortic stiffness) were assessed longitudinally by echocardiography from day 1 through week 8. A mixed ANOVA with repeated measures was performed to compare findings between groups across time. Myocardial hematoxylin and eosin and picro-sirius staining were performed to evaluate myocyte nuclear shape and collagen fiber characteristics, respectively.
Results:
Systolic function parameters transiently increased following hypoxia exposure primarily at week 2 (p < .008). In contrast, diastolic dysfunction progressed following fetal hypoxia exposure beginning weeks 1-2 with lower early inflow Doppler velocities, and less of an increase in early to late inflow velocity ratios and annular and septal E'/A' tissue velocities compared to controls (p < .008). As further evidence of altered diastolic function, isovolumetric relaxation time was significantly shorter relative to the cardiac cycle following hypoxia exposure from week 1 onward (p < .008). Aortic stiffness was greater following hypoxia from day 1 through week 8 (p < .008, except week 4). Hypoxia exposure was also associated with altered nuclear shape at week 2 and increased collagen fiber thickness at week 4.
Conclusion:
Chronic fetal hypoxia is associated with progressive LV diastolic dysfunction, which corresponds with changes in nuclear shape and collagen fiber thickness, and increased aortic stiffness from early postnatal stages.
... We speculate that a secondary lifestyle insult such as a high salt or high fat diet may be required to induce overt signs of disease following PC:EtOH. Salt sensitive hypertension has been demonstrated during a high sodium challenge in rats following a prenatal low protein diet (Woods et al. 2004), and in our model of PC:EtOH, we have recently demonstrated that a Western style diet exacerbates the metabolic outcomes, including the development of obesity in male offspring (Gardebjer et al. 2015;. This highlights the ability of postnatal insults to exacerbate underlying conditions following prenatal perturbations. ...
Maternal alcohol consumption can impair renal development and program kidney dysfunction in offspring. Given that most women who drink alcohol cease consumption upon pregnancy recognition, we aimed to investigate the effect of alcohol around the time of conception (PC:EtOH) on offspring renal development and function. Rats received a liquid diet ±12.5% v/v ethanol from 4 days before to 4 days after mating. At postnatal day 30, nephron number was assessed. Urine flow and electrolyte (Na, K, Cl) excretion was measured at 6 and 19 months and blood pressure at 12 months. At 19 months, kidneys were collected for gene and protein analysis and assessment of collecting duct length. At postnatal day 30, PC:EtOH offspring had fewer nephrons. At 6 months, PC:EtOH exposure did not alter urine flow nor affect blood pressure at 12 months. At 19 months, female but not male offspring exposed to PC:EtOH drank more water and had a higher urine flow despite no differences in plasma arginine vasopressin (AVP) concentrations. Aqp2 mRNA and Avpr2 mRNA and protein expression was increased in kidneys from female PC:EtOH offspring but collecting duct lengths were similar. Immunofluorescent staining revealed diffuse cytoplasmic distribution of AQP2 protein in kidneys from PC:EtOH females, compared with controls with apical AQP2 localization. PC:EtOH resulted in a low nephron endowment and in female offspring, associated with age-related diuresis. Changes in expression and cellular localization of AQP2 likely underpin this disturbance in water homeostasis and highlight the need for alcohol to be avoided in early pregnancy.
... We previously showed that maternal nutrient restriction suppressed ureteric branching during the fetal period and induced low glomerular number in adult kidneys. Male rats were examined because the effect of programming is stronger in males than females in general [12]. Also most of our current knowledge of UUO has been obtained from studies using male rats. ...
Maternal undernutrition is known to reduce glomerular number but it may also affect tubulointerstitium, capillary density, and response to oxidative stress. To investigate whether the latter elements are affected, we examined the response to unilateral ureteral obstruction (UUO), an established model of renal tubulointerstitial fibrosis, in the kidney of offspring from control and nutrient restricted rats. Six-week old male offspring from rats given food ad libitum (CON) and those subjected to 50% food restriction throughout pregnancy (NR) were subjected to UUO for 7 days. Body weight was significantly lower in NR. Systolic blood pressure and blood urea nitrogen increased similarly in CON and NR after UUO. Tubular necrosis in the obstructed kidney, on the other hand, was more extensive in NR. Also, the collagen area, a marker of fibrosis, of the obstructed kidney was significantly increased compared with the contralateral kidney only in NR. Capillary density was decreased similarly in the obstructed kidney of CON and NR compared with the contralateral kidney. Urine nitrate/nitrite, a marker of nitric oxide production, from the obstructed kidney was significantly increased in NR compared with CON. Nitrotyrosine, a marker of nitric oxide-mediated free radical injury, was increased in the obstructed kidney compared with the contralateral kidney in both CON and NR, but the extent was significantly greater in NR. In conclusion, more severe tubular necrosis and fibrosis after UUO was observed in NR, which was thought to be due to increased nitrosative stress.
... A less severe maternal protein diet of 8.5% during pregnancy resulted in elevated blood pressure in male but not female adult offspring (Woods et al. 2001(Woods et al. , 2005. Woods et al. found that a more severe maternal protein restriction to 5% resulted in hypertension in both male and female offspring (Woods et al. 2004). Others have examined if there was a sex difference in blood pressure utilizing the uteroplacental insufficiency model of prenatal programming. ...
We have previously demonstrated that dexamethasone administered to pregnant rats during specific times during gestation results in a reduction in glomerular number and hypertension in offspring at 2 and 6 months of age. In this study, we examined the effect of prenatal dexamethasone administered daily on days 15 and 16 of gestation in male and female offspring after 1 year of age on glomerular filtration rate. The prenatal dexamethasone male group had a higher systolic blood pressure than the vehicle male group. Females had lower systolic blood pressures than the males and prenatal dexamethasone did not affect blood pressure in female offspring. Prenatal dexamethasone resulted in a reduction in glomerular filtration rate in male but not in female rats. When corrected for body weight, the control male rats had a lower glomerular filtration rate than the control female rats. Males had greater protein excretion than females and prenatal dexamethasone increased the protein excretion only in male rats. Glomerulosclerosis was also greater in male rats than females but was not affected by prenatal dexamethasone. In summary, male rats appear to have evidence of a decline in glomerular filtration rate after 1 year of age and prenatal dexamethasone programs an accelerated decline in glomerular filtration rate in male but not in female offspring. This study shows that prenatal programming by dexamethasone causes a reduction in glomerular filtration rate in males but not female rats.
... Being born preterm interrupts development at a critical stage, as the final development of systemic processes and structures that regulate BP (including the renin-angiotensin system and kidney nephrons) are only completed in the late stages of gestation, so that a premature birth results in abnormalities that impair the individual's ability to adequately regulate BP. 21 This association has been demonstrated in animal models, where a reduction in nephron numbers alone was associated with hypertension later in life, [22][23][24] with similar observations reported in humans. 25 In addition, arterial wall elastin synthesis peaks towards the end of gestation, 26 which is particularly important for the development of the arterial tree that, in turn, has a crucial role in maintaining normotension. ...
Background
While there is some evidence of elevated blood pressure later in life in preterm survivors, data on adult women are still lacking. Thus, we assessed the associations between preterm birth and blood pressure in young adult women.
Methods and Results
We studied 5232 young adult women who volunteered for military service in Sweden between 1990 and 2007. Anthropometric and clinic blood pressure data were collected during the medical examination at the time of conscription. There was a progressive decline in systolic and diastolic blood pressures, as well as in mean arterial pressure, with increasing gestational age. Women born preterm had an adjusted increase in systolic blood pressure of 3.8 mm Hg (95% CI , 2.5–5.1; P <0.0001) and mean arterial pressure of 1.9 mm Hg (95% CI , 0.9–2.8; P =0.0001) compared with young women born at term. Rates of systolic hypertension were also considerably higher in young women born preterm (14.0% versus 8.1%, P <0.0001), as were rates of isolated systolic hypertension. The adjusted relative risk of systolic hypertension in women born preterm was 1.72 (95% CI , 1.26–2.34; P <0.001) that of women born at term or post‐term, but there was no significant difference in the risk of diastolic hypertension (adjusted relative risk, 1.60; 95% CI , 0.49–5.20).
Conclusions
Young adult women born preterm display elevated systolic blood pressure and an increased risk of hypertension compared with peers born at term or post‐term.
... Because cKO mice exhibit reduced nephron number at birth, a known determinant of susceptibility to hypertension both in animals and humans (1,39), we evaluated the effect of reduced stromal PRR gene dosage in Het mice on blood pressure at 2 mo of age. Het mice were used because cKO mice died within 24 -48 h after birth. ...
Formation of the metanephric kidney requires coordinated interaction among the stroma, ureteric bud and cap mesenchyme. The transcription factor Foxd1, a specific marker of renal stromal cells, is critical for normal kidney development. The prorenin receptor (PRR), a receptor for renin and prorenin, is also an accessory subunit of the vacuolar proton pump V-ATPase. Global loss of PRR is embryonic lethal in mice, indicating an essential role of the PRR in embryonic development. Here, we report that conditional deletion of the PRR in Foxd1+ stromal progenitors in mice ( cKO) results in neonatal mortality. The kidneys of surviving mice show reduced expression of stromal markers Foxd1 and Meis1, and a marked decrease in arterial and arteriolar development with the subsequent decreased number of glomeruli, expansion of Six2+ nephron progenitors and delay in nephron differentiation. Intrarenal arteries and arterioles in cKO mice were fewer, thinner and showed a marked decrease in the expression of renin, suggesting a central role for the PRR in the development of renin expressing cells, which in turn are essential for the proper formation of the renal arterial tree. We conclude that stromal PRR is crucial for the appropriate differentiation of the renal arterial tree which, in turn, may restrict excessive expansion of nephron progenitors to promote a coordinated and proper morphogenesis of the nephrovascular structures of the mammalian kidney.
... The first observations dated from 1998 found that renal development and the number of nephrons was lower when animal models have had a diet with low protein content (Langley-Evans et al., 1999;Woods, Weeks, & Rasch, 2004). This reduced proliferation reduces the activities associated with the renal filtration surface; consequently, as a compensatory mechanism to this oligonephrony , glomerular hypertrophy significantly affects renal activity Mackenzie & Brenner, 1995;Paixão et al., 2001). ...
The hypothalamic‐pituitary‐adrenal (HPA) axis is an important hormonal mechanism of the human body and is extremely programmable during embryonic and fetal development. Analyzing its development in this period is the key to understanding in fact how vulnerabilities of congenital diseases occur and any other changes in the phenotypic and histophysiological aspects of the fetus. The environment in which the mother is exposed during the gestational period can influence this axis. Knowing this, our objective was to analyze in recent research the possible impact of epigenetic programming on the HPA axis and its consequences for fetal development. This review brought together articles from two databases: ScienceDirect and PUBMED researched based on key words such as “epigenetics, HPA axis, cardiovascular disease, and circulatory problems” where it demonstrated full relevance in experimental and scientific settings. A total of 101 articles were selected following the criteria established by the researchers. Thus, it was possible to verify that the development of the HPA axis is directly related to changes that occur in the cardiovascular system, to the cerebral growth and other systems depending on the influence that it receives in the period of fetal formation.
... Increased propensity to develop hypertension may be determined during early stages of life that include the intrauterine period, infancy and childhood [1]. Perturbations during gestation and lactation that induce low birth weight of offspring have been studied in fetal programming of hypertension [2][3][4][5]. Administration of high sucrose during pregnancy and before it in addition to its administration during lactation and the first days after weanling elevated susceptibility to develop hypertension when adulthood was reached [6]. A diet containing high salt before and during pregnancy, lactation and the early weaning period also elevated the susceptibility to high blood pressure when rats reached the adult age [7]. ...
Susceptibility to develop hypertension may be established during early stages of life that include the intrauterine period, infancy and childhood. We recently showed that blood pressure increased when rats reached adulthood when sucrose was ingested for a short-term critical window from postnatal day 12 to 28 in the rat, which corresponds to days around weaning. Here, we studied several factors that might participate in the increased susceptibility to hypertension when adulthood is reached by analyzing the changes produced at the end of the sucrose ingestion during this critical period. Body weight of the rats at the end of the sucrose period was decreased even if there was an increased ingestion in Kcal. We found an increase in blood pressure accompanied by a decrease in endothelial nitric oxide synthase (eNOS) expression in the aorta. When insulin was administered to rats receiving sucrose, glucose in plasma diminished later than in controls and this slight insulin resistance may reduce nitric oxide synthase action. Oleic acid that modulates eNOS expression was increased, lipoperoxidation was elevated and total non-enzymatic anti-oxidant capacity was decreased. There was also a decrease in SOD2 expression. We also studied the expression of Sirt1, which regulates eNOS expression and Sirt3, which regulates SOD2 expression as possible epigenetic targets of enzyme expression involved in the long- term programming of hypertension. Sirt3 was decreased but we did not find an alteration in Sirt1 expression. We conclude that these changes may underpin the epigenetic programming of increased susceptibility to develop hypertension in the adults when there was exposure to high sucrose levels near weaning in rats.
The concept of the early life developmental origins of health and disease (DOHaD) in adults has stimulated a new approach to understanding disease trajectories, with major public health implications. Indeed, the principle of the 'lifecourse of disease' now influences health policies internationally. Environmental influences during pregnancy and early life that affect lifelong health are well documented, but there is a new focus on the preconception period and the significance of paternal health on the fetus. This fully revised second edition highlights scientific and clinical advances in the field, exploring new understanding of mechanisms such as epigenetics and the increasingly recognised role of external influences, including pollution. The book is structured logically, covering environment, clinical outcomes, mechanisms of DOHaD, interventions throughout the lifespan and finally implications for public health and policy. Clinicians and scientists alike will improve their understanding of the developmental origins of health and disease with this essential text.
Children born to women who experience stress during pregnancy have an increased risk of atherosclerosis in later life, but few animal models have explored mechanisms. To study this phenomena, timed-bred ApoE knockout mice were determined pregnant with ultrasound and randomly assigned on gestation day 8.5 to either a control (no stress) or prenatal stress (PS) group using two hours of restraint for five consecutive days. PS significantly increased plasma corticosterone levels in pregnant mice. The litters from PS mice showed increased neonatal mortality within the first week of life. Body weights (at euthanasia) of adult offspring at 25 weeks from the PS group were significantly increased compared to weights of controls. Adult offspring from these pregnancies were serially imaged with ultrasound to measure plaque thickness and were compared with plaque macro- and microscopic pathology. PS groups had increased plaques thickness by ultrasound, gross, histological evaluation and increased aortic root and valve macrophage infiltration at 25 weeks. Five-week old mice from PS group had significant decrease in mean arterial pressure, yet blood pressure normalized by 10 weeks. Since prenatal stress induced increased atherosclerosis, and telomeres are susceptible to stress, aortas from 10 week old mice were compared for telomere lengths and were found to be significantly shorter in PS mice compared to control mice. These studies support future investigation of how stress impacts telomere shortening in animal models and human aortas. This model could be further utilized to investigate the role of prenatal stress, telomere biology and atherosclerosis pathogenesis in adults.
Nutritional management and dietary intake have a major impact on kidney health and longevity. Among the macronutrients a large body of evidence has shown that increased dietary protein engenders changes in renal hemodynamics, kidney function, and kidney morphology. It has also been shown that various individual amino acids may have differential effects on kidney function, according to their site of metabolism. There has also been growing interest in the impact of dietary protein sources on kidney health outcomes, with more salutary benefits observed with plant-based, low-fat dairy, and white meat sources as opposed to red meat sources. Multiple concurrent mechanisms may mediate the protein- and amino acid–induced changes in kidney function and morphology, including endocrine factors (e.g., growth hormone, insulin-like growth factor-1, glucagon, renin–angiotensin–aldosterone, dopamine, atrial peptides) or local mediators (e.g., eicosanoids, nitric oxide). To date, the direct impact of dietary carbohydrate and fat intake on kidney function and structure has not been well studied, but emerging evidence suggests potential associations between the dietary intake of these macronutrients, including amount and type, with the development and progression of chronic kidney disease (CKD). In the nonkidney disease population, certain dietary patterns [e.g., Dietary Approaches to Stop Hypertension (DASH), Mediterranean diets] have been endorsed by clinical practice guidelines given their favorable effects on hypertension, diabetes, cardiovascular risk, and survival and long-term sustainability. As examination of dietary patterns provides a more comprehensive and synergistic assessment of nutritional status in lieu of single nutrients, an increasing number of studies have also examined the impact of the DASH and Mediterranean diets on the development and progression of CKD.
The global burden of chronic kidney disease (CKD) is rising. A superior strategy to advance global kidney health is required to prevent and treat CKD early. Kidney development can be impacted during the first 1000 days of life by numerous factors, including malnutrition, maternal illness, exposure to chemicals, substance abuse, medication use, infection, and exogenous stress. In the current review, we summarize environmental risk factors reported thus far in clinical and experimental studies relating to the programming of kidney disease, and systematize the knowledge on common mechanisms underlying renal programming. The aim of this review is to discuss the primary and secondary prevention actions for enhancing kidney health from pregnancy to age 2. The final task is to address the potential interventions to target renal programming through updating animal studies. Together, we can enhance the future of global kidney health in the first 1000 days of life.
A balanced diet with adequate nutrient intake is vital for normal fetal kidney development to occur. In contrast, maternal malnourishment during pregnancy impairs fetal kidney development due to a deficiency in nutrients that the mother and growing fetus have access to. Nutritional deficiency not only reduces the structural building blocks needed for nephron generation but also impacts various signaling pathways, growth factors, epigenetic modifications, gene expression, and oxidative stress that collectively blunts nephrogenesis. These effects of nutritional deficiency consequently reduce the stem cell pool that is available for nephron building by altering their self-renewal, survival, and patterned differentiation. As a result, the fetus is born following maternal malnourishment with significantly fewer nephrons, underdeveloped kidneys, potential kidney dysfunction, and a lifelong increased susceptibility to kidney and cardiovascular disease. Discussed in this chapter are the specific affects that vitamins, minerals, amino acids, lipids, and fatty acids have on stem cells, nephrogenesis, and kidney development.
Prenatal dexamethasone has been shown to increase blood pressure in male offspring but the mechanism for the increase in blood pressure is unclear. The present study examined if prenatal programming by maternal injection of dexamethasone on days 15 and 16 of gestation affected the blood pressure comparably in female and male offspring. Our hypothesis was that males would be affected by prenatal dexamethasone to a greater extent than females and that either an increase in renal tubular transporter abundance or an increase in renin or aldosterone system would be associated with hypertension with prenatal programming. Prenatal dexamethasone increased blood pressure at two months and six months of age and resulted in proteinuria and albuminuria at six months in male but not female rat offspring. There was no effect of prenatal dexamethasone on blood pressure and proteinuria at one month in male and in female offspring. While prenatal dexamethasone increased male renal thick ascending limb sodium potassium two chloride cotransporter protein abundance at two months, prenatal dexamethasone on days 15 and 16 of gestation did not affect transporter abundance in males at other ages, nor did it affect proximal tubule sodium/hydrogen exchanger or distal convoluted tubule sodium chloride cotransporter protein abundance at any age. There was no difference in systemic renin or aldosterone in the prenatal dexamethasone group compared to same sex controls. In conclusion, male but not female offspring have an increase in blood pressure and urinary protein excretion with prenatal dexamethasone. The increase in blood pressure with prenatal programming was not associated with a consistent increase in renal tubular transporter protein abundance, nor plasma renin activity and serum aldosterone.
Preclinical evidence suggests that adult blood pressure (BP) may be modified by the prenatal endocrine environment. Specifically, in several animal models, higher prenatal testosterone exposure increases the risk of hypertension in later life. We investigated the prospective association between prenatal testosterone levels (as measured in umbilical cord blood) and BP at 20 to 27 years in 434 participants from the Raine Study. As expected, median bioavailable testosterone, the fraction of total testosterone either free or bound to serum albumin, was higher in males than females (0.12 [Q1–Q3, 0.09–0.19] versus 0.07 [Q1–Q3, 0.05–0.1] nmol/L; P <0.001). Mean (SD) systolic BP was 122.9 (±12.3) and 110.9 (±9.5) mm Hg at age 20 years and 122.4 (±11) and 111.2 (±9.1) mm Hg at 27 years in males and females, respectively. Using hierarchical mixed-effects models, higher cord blood bioavailable testosterone concentrations were associated with higher levels of systolic BP ( P =0.007) and diastolic BP ( P =0.002) in young adults at 20 and 27 years, after adjusting for change in BP over time and potential confounders. In these models, one SD increase in bioavailable testosterone equated to a 1 mm Hg increase in systolic BP (regression coefficient, 11.1 [95% CI, 4.1–21.11]) and diastolic BP (regression coefficient, 10.15 [95% CI, 3.67–15.93]). There was no significant difference detected between males and females in the association between bioavailable testosterone and adult BP. These data from a large unselected population indicate that higher fetal testosterone levels in late pregnancy are associated with higher BP in young adulthood.
In the last years, great advances have been made in the effort to understand how nutritional influences can affect long-term renal health. Evidence has accumulated that maternal nutrition before and during pregnancy and lactation as well as early postnatal nutrition is of special significance. In this review, we summarize epidemiologic and experimental data on the renal effects of perinatal exposure to energy restriction, low-protein diet, high-fat diet, high-fructose diet, and high- and low-salt diet as well as micronutrient deficiencies. Interestingly, different modifications during early-life diet may end up with similar sequelae for the offspring. On the other hand, molecular pathways can be influenced in opposite directions by different dietary interventions during early life. Importantly, postnatal nutrition significantly modifies the phenotype induced by maternal diet. Sequelae of altered macro- or micronutrient intakes include altered nephron count, blood pressure dysregulation, altered sodium handling, endothelial dysfunction, inflammation, mitochondrial dysfunction, and oxidative stress. In addition, renal prostaglandin metabolism as well as renal AMPK, mTOR, and PPAR signaling can be affected and the renin-angiotensin-aldosterone system may be dysregulated. Lately, the influence of early-life diet on gut microbiota leading to altered short chain fatty acid profiles has been discussed in the etiology of arterial hypertension. Against this background, the preventive and therapeutic potential of perinatal nutritional interventions regarding kidney disease is an emerging field of research. Especially individuals at risk (e.g., newborns from mothers who suffered from malnutrition during gestation) could disproportionately benefit from well-targeted dietary interventions.
Studies of human nephron number have been conducted for well over a century and have uncovered a large variability in nephron number. However, the mechanisms influencing nephron endowment and loss, along with the etiology for the wide range among individuals are largely unknown. Advances in imaging technology have allowed investigators to revisit the principles of renal structure and physiology and their roles in the progression of kidney disease. Here, we will review the latest data on the influences impacting nephron number, innovations made over the last 6 years to understand and integrate renal structure and function, and new developments in the tools used to count nephrons in vivo.
Background and objectives
Famine exposure in human early life is proven to be associated with urinary protein concentration and renal function but has not been studied with chronic kidney disease. We aimed to explore the association between exposure to the Chinese famine (from 1959 to 1962) in early life and the risk of chronic kidney disease in adulthood.
Design, setting, participants, and measurements: We selected 6267 participants from the baseline survey of China Health and Retirement Longitudinal Study (CHARLS) 2011–2012. Based on the birth year, they were divided into fetal exposed, preschool exposed, school-aged exposed, and non-exposed groups. The estimated glomerular filtration rate (eGFR) was calculated according to Japanese coefficient–modified Chronic Kidney Disease Epidemiology Collaboration equation. Chronic kidney disease (CKD) was defined as eGFR less than 60 mL/min per 1.73 m².
Results
The prevalence of CKD in fetal exposed, preschool exposed, school-aged exposed and non-exposed groups was 4.27%, 5.41%, 9.65% and 2.42%, respectively. The risk of CKD in fetal exposed, preschool exposed and school-aged exposed groups was significantly higher than the non-exposed group. In addition, after stratification by gender and famine severity, we found that only fetal exposure to the severe famine was associated with the elevated risk of CKD among male adults (OR 4.44, 95%CI 1.10–17.92, P < 0.05), even after adjusting for age, marital status, household per capita income, history of kidney disease, hypertension, diabetes or abnormal glucose tolerance, smoking, drinking, rural/urban residence and highest educational attainment of parents.
Conclusions
Severe famine exposure as a fetus might increase the risk of chronic kidney disease in male adults.
Studies with animal models have consistently demonstrated adverse health outcomes in offspring born following nutritional manipulation during gestation. However, the effects of gestational dietary protein modification on reproductive outcomes at birth are less clear. We, therefore, conducted a systematic review and meta-analysis of controlled trials to determine if high or low protein diets are associated with altered reproductive outcomes in a commonly studied species, the rat. Included studies were identified through a systematic search using electronic databases and manual literature review to identify randomized studies published between June 1972 and March 2019. Thirty two studies were identified and used to analyse the effects of low and high protein gestational diets on litter size, litter weight, gestational weight gain, and gestational feed intake. The results indicate that low protein diets significantly reduced litter weight (p<0.00001) and gestational weight gain (p<0.0006), but did not influence litter size (p=0.62) or gestational feed intake (p=0.25). In contrast, high protein diets were found to reduce gestational feed intake (p=0.004) but did not influence litter size (p=0.56), litter weight (p=0.22) or gestational weight gain (p=0.35). The results suggest that low but not high protein gestational diets alter reproductive outcomes at birth in rats.
The worldwide increase in metabolic diseases has urged the scientific community to improve our understanding about the mechanisms underlying its cause and effects. A well supported area of studies had related maternal stress with early programming to the later metabolic diseases. Mechanisms upon origins of metabolic disturbances are not yet fully understood, even though stressful factors rising glucocorticoids have been put out as pivotal trigger by programming metabolic diseases as long-term consequence. Considering energy balance and glucose homeostasis, by producing and/or sensing regulator signals, hypothalamus-pituitary-adrenal axis and endocrine pancreas are directly affected by glucocorticoids excess. We focus on the evidences reporting the role of increased glucocorticoids due to perinatal insults on the physiological systems involved in the metabolic homeostasis and in the target organs such as endocrine pancreas, white adipose tissue and blood vessels. Besides, we review some mechanisms underlining the malprogramming of type 2 diabetes, obesity and hypertension. Studies on this field are currently ongoing and even there is a good understanding regarding the effects of glucocorticoids addressing metabolic diseases, few is known about the relationship between maternal insults rising glucocorticoids to pups' metabolic disturbances, a thorough understanding about that may provide pivotal clinical clues regarding those disorders.
To determine how fetal growth is related to death from cardiovascular disease in adult life.
A follow up study of men born during 1907-24 whose birth weights, head circumferences, and other body measurements were recorded at birth.
Sheffield, England.
1586 Men born in the Jessop Hospital.
Death from cardiovascular disease.
Standardised mortality ratios for cardiovascular disease fell from 119 in men who weighed 5.5 pounds (2495 g) or less at birth to 74 in men who weighed more than 8.5 pounds (3856 g). The fall was significant for premature cardiovascular deaths up to 65 years of age (chi 2 = 5.0, p = 0.02). Standardised mortality ratios also fell with increasing head circumference (chi 2 = 4.6, p = 0.03) and increasing ponderal index (weight/length3) (chi 2 = 3.8, p = 0.05; for premature deaths chi 2 = 6.0, p = 0.01). They were not related to the duration of gestation. Among men for whom the ratio of placental weight to birth weight was in the highest fifths the standardised mortality ratio was 137.
These findings show that reduced fetal growth is followed by increased mortality from cardiovascular disease. They suggest that reduction in growth begins early in gestation. They are further evidence that cardiovascular disease originates through programming of the body's structure, physiology, and metabolism by the environment during fetal life. Maternal nutrition may have an important influence on programming.
Objective-To determine whether the relation between high blood pressure and low birth weight is initiated in utero or during infancy, and whether it changes with age. Design-A longitudinal study of children and three follow up studies of adults. Setting-Farnborough, Preston, and Hertfordshire, England, and a national sample in Britain. Subjects-1895 children aged 0-10 years, 3240 men and women aged 36 years, 459 men and women aged 46-54 years, and 1231 men and women aged 59-71 years. The birth weight of all subjects had been recorded. Main outcome measure-Systolic blood pressure. Results-At all ages beyond infancy people who had lower birth weight had higher systolic blood pressure. Systolic blood pressure was not related to growth during infancy independently of birth weight. The relation between systolic pressure and birth weight became larger with increasing age so that, after current body mass was allowed for, systolic pressure at ages 64-71 years decreased by 5.2 mm Hg (95% confidence interval 1.8 to 8.6) for every kg increase in birth weight. Conclusions-Essential hypertension is initiated in fetal life. A raised blood pressure is then amplified from infancy to old age, perhaps by a positive feedback mechanism.
Described are a macromethod for measuring 2 to 30 mug of polyfructoside in sample volumes of 0.5 ml and a micromethod for measuring 40 to 400 ng in 10-mul samples. The absorptivity of the cysteine/tryptophan color product is 2.5-to 10-fold those found with use of five other colorimetric methods for inulin. The method is highly specific for alkali-stable polyfructoside. Color, measured at 515 nm, was maximal on development at 56 degrees C for 25 min in dilute (57-58% by vol) sulfuric acid, after the addition of the combined cysteine hydrochloride/tryptophan reagent. Analytical recoveries of inulin and polyfructosan from plasma and urine were complete. With initial alkaline heating, the endogenous blank inulinoid values averaged 0.6 +/- 0.47 (SD) mg/liter for plasma and 0.05 +1- 0.024 mg/min for urine. The coefficient of variation of the macromethod was less then 3%; that for the micromethod ranged from 1.3 to 6.3%. The micromethod appears adaptable to the determination of nanogram quantities of polyfructoside in nanoliter volumes of biological fluids.
The number and size of glomeruli in normal, mature human kidneys were estimated by a direct and unbiased stereological method, the fractionator. The number was 617,000 on average, and the mean size 6.0 M μm3. Both glomerular number and size showed significant negative correlation to age and significant positive correlation to kidney weight. Apparently, humans loose glomeruli with age.
Body surface area correlated positively to kidney weight and total glomerular volume but not to number of glomeruli. Body surface area correlates significantly with metabolic rate (Robertson and Reid, Lancet, 1: 940–943, 1952). Thus, intraspecies adaptation of kidney filtration capacity to the metabolic demand is performed by changing the size of glomeruli, i. e., the number of glomeruli in individuals of a given species is independent of the metabolic rate.
The disector method, a stereologic procedure unbiased by feature size, shape, or tissue-processing methods, for the estimation of total glomerular number was performed on pairs of human kidneys from 11 normal spontaneous second trimester abortions and stillbirths (15 to 40 weeks gestation). In addition, gestational age-dependent patterns of change in the average volume of the nephron and its cortical and medullary segments were analyzed. Mean glomerular number, plateauing at 36 weeks, increased from 15,000 at 15 weeks to 740,000 at 40 weeks. Average volume of the medullary nephron segment (Henle's loop) increased throughout pregnancy. Average volume of the cortical nephron segment (Tubuli Contorti) decreased from 15 weeks to 25 weeks, then increased after 36 weeks. Fractional volume of the renal cortex decreased from 15 weeks to 40 weeks. Three to 4 hours of microscopic analysis time were required per kidney on routinely processed 5-μm hematoxylin and eosin-stained paraffin sections. Average coefficient of error for number estimation was 8.02%. Average intra- and interobserver reproducibilities were 96.8 and 93.7%, respectively. The demonstrated temporal differences in the development of the cortical and medullary nephron components may result in a dissociation of function, which may explain the increased incidence of fetal hydrops in the second trimester of pregnancy, and which must be taken into account in the treatment of (very) premature infants. Although the number of kidneys included in this study is limited, as they reflect the whole period of antenatal development relevant to neonatal intensive care, the disector method of glomerular number estimation shows significant potential for the analysis and increased understanding of the development of renal function. The method appears to be more sensitive in detecting small and early deviations from normal renal growth and development than previously available parameters e.g., renal weight and (cortical) volume.
To study the effect of intrauterine growth and maternal physique on blood pressure in adult life.
A follow up study of infants born 50 years previously whose measurements at birth were recorded in detail.
Preston, Lancashire.
449 Men and women born in hospital in Preston during 1935-43 and still living in Lancashire.
Placental weight, birth weight, and blood pressure at age 46 to 54 years.
In both sexes systolic and diastolic pressures were strongly related to placental weight and birth weight. Mean systolic pressure rose by 15 mm Hg as placental weight increased from less than or equal to 1 lb (0.45 kg) to greater than 1.5 lb and fell by 11 mm Hg as birth weight increased from less than or equal to 5.5 lb to greater than 7.5 lb. These relations were independent so that the highest blood pressures occurred in people who had been small babies with large placentas. Higher body mass index and alcohol consumption were also associated with higher blood pressure, but the relations of placental weight and birth weight to blood pressure and hypertension were independent of these influences.
These findings show for the first time that the intrauterine environment has an important effect on blood pressure and hypertension in adults. The highest blood pressures occurred in men and women who had been small babies with large placentas. Such discordance between placental and fetal size may lead to circulatory adaptation in the fetus, altered arterial structure in the child, and hypertension in the adult. Prevention of hypertension may depend on improving the nutrition and health of mothers.
Environmental influences that impair growth and development in early life may be risk factors for ischaemic heart disease. To test this hypothesis, 5654 men born during 1911-30 were traced. They were born in six districts of Hertfordshire, England, and their weights in infancy were recorded. 92.4% were breast fed. Men with the lowest weights at birth and at one year had the highest death rates from ischaemic heart disease. The standardised mortality ratios fell from 111 in men who weighed 18 pounds (8.2 kg) or less at one year to 42 in those who weighed 27 pounds (12.3 kg) or more. Measures that promote prenatal and postnatal growth may reduce deaths from ischaemic heart disease. Promotion of postnatal growth may be especially important in boys who weigh below 7.5 pounds (3.4 kg) at birth.
A primary role for the kidney in the initiation and maintenance of hypertension has long been recognized, but the pathogenetic interactions among renal hemodynamics, hormonal and hereditary factors, and dietary sodium intake remain enigmatic. Reduction in filtration surface area, whether acquired in the course of intrinsic renal disease or after surgical renal ablation, leads to systemic hypertension as well as to progressive renal insufficiency, sequellae made even more severe by dietary sodium excess. Moreover, hypertension and progressive renal disease eventuate in some individuals born with a solitary kidney, as well as in those with more severe degrees of dysgenesis (ie, oligomeganephronia). Hypertension is also commonly observed in certain inbred rat strains in which filtration surface area is congenitally deficient. Based on these and other lines of evidence reviewed herein, we postulate that a renal abnormality that contributes to essential hypertension in the general population is a reduced number of nephrons. The consequences of this abnormality are limitations in the ability to excrete sodium and thus, salt-sensitive hypertension. Finally, congenital variability in filtration surface area may explain why only some, but not all, patients exposed to potentially injurious renal stimuli eventually manifest chronic nephropathy. This may also account for the susceptibility of subsets of Type I and Type II diabetics to develop overt glomerulopathy.
Kidney International aims to inform the renal researcher and practicing nephrologists on all aspects of renal research. Clinical and basic renal research, commentaries, The Renal Consult, Nephrology sans Frontieres, minireviews, reviews, Nephrology Images, Journal Club. Published weekly online and twice a month in print.
Sprague-Dawley rats were nephrectomized unilaterally, or sham-operated at 5, 12, and 40 days of age. The kidney weight, number of glomeruli, GFR, and single nephron GFR (SNGFR) were determined in about 60 days of age. In both sham-operated and nephrectomized rats operated on at 5 and 12 days of age, the kidney was studied with light microscope for 1 to 14 days. Unilateral nephrectomy performed just before or just after completion of nephrogenesis or in adulthood did not result in formation of new nephrons. Renal structural development followed the same pattern in nephrectomized and sham-operated rats. A compensatory increase in renal size and GRF was inversely related to the age at which the nephrectomy was carried out but was more pronounced if nephrectomy had been performed just before rather than just after completion of nephrogenesis. In all nephrectomized rats, the compensatory increase in filtration rate appears to be the same in nephrons at all cortical levels judging by comparison of SNGRR and GFR. Conclusion. Compensatory renal growth does not involve the formation of new nephrons in the postnatal kidney of the rat. The potentiation of compensatory changes after nephrectomy at an early age is largely dependent on the development stage of the kidney at the time of nephrectomy.
In 1988, Brenner et al advanced the hypothesis that the nephron endowment at birth is inversely related to the risk of developing essential hypertension in later life (Am J Hypertens 1:335-347, 1988). This novel perspective on the origins of essential hypertension was taken from the viewpoint that the development and maintenance of hypertension must involve a renal factor favoring sodium retention, thereby preventing pressure-induced natriuresis from restoring blood pressure toward normal levels. Since nephron numbers in the normal population range from 300,000 to 1,100,000 or more, it was reasoned that a congenital deficit in nephron endowment itself could be the renal risk factor for hypertension: demographic groups in whom hypertension is unusually prevalent tend to have smaller kidneys, implying fewer nephrons, and some inbred hypertensive rat strains have, on average, fewer nephrons than their respective normotensive controls. We argue that recent independent observations in humans relating low birth weight to both increased risk of hypertension in later life and the formation of fewer nephrons at birth lend strong support to the nephron number hypothesis. Moreover, independent experimental studies in rodents suggest that maternal protein intake during gestation is directly related to he numbers of nephrons formed and that when protein intake is restricted, the offspring develop hypertension in maturity. The concept that nephron numbers may be programmed during gestation, as these observations imply, is discussed in relation to the potential advantages and disadvantages of such a mechanism for the next generation; parallels are drawn with the relationship of low birth weight to pancreatic beta cell development and maturity-onset diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)
1. Possible associations between maternal nutrition in pregnancy and non-communicable diseases of adulthood were assessed using a rat model. Rats were habituated to diets containing a range of protein levels (18, 12, 9 and 6% by weight), over a 14 day period, before mating. The low protein diets were maintained throughout pregnancy. Lactating mothers and their offspring were transferred to a standard chow diet (20% protein).
2. Pregnant rats demonstrated a graded response to the diets, with those fed 9 and 6% protein tending to consume less energy and gain less weight than 18% protein fed controls. Litter size and newborn death rates were not significantly altered by the low protein diets.
3. Offspring of 12 and 9% protein fed dams were grossly normal, gaining weight at a similar rate to those born to 18% protein fed control rats. Offspring of the 6% protein fed dams were smaller than pups from all other groups, over a 21 week period.
4. At 9 weeks of age, systolic blood pressure was determined in the offspring. All offspring from the three low protein groups were found to have significantly elevated blood pressure (15–22 mmHg) relative to the control group. An inverse relationship between maternal protein intake and the systolic blood pressure of the offspring was observed. Blood pressure remained elevated in the offspring of the 9 and 6% protein fed dams until 21 weeks of age. The observed hypertension was associated with increased pulmonary angiotensin-converting enzyme activity in the low protein groups.
5. The data are consistent with the hypothesis that poor maternal nutrition in pregnancy may irreversibly impair aspects of physiological and biochemical function in the fetus. This has potential adverse consequences for the later health of the offspring.
Based on the associations reviewed in this report, we have hypothesized that retardation of renal development as occurs in individuals of low birth weight gives rise to increased postnatal risks for systemic and glomerular hypertension as well as enhanced risk of expression of renal disease. This hypothesis draws on observations suggesting (1) a direct relationship between birth weight and nephron number, (2) an inverse relationship between birth weight and later-life hypertension, and (3) an inverse relationship between nephron number and blood pressure, irrespective of whether nephron number is reduced congenitally or in postnatal life (as from partial renal ablation or acquired renal disease). Additional clinical and epidemiologic studies are needed to assess these initial impressions.
To determine whether the relation between high blood pressure and low birth weight is initiated in utero or during infancy, and whether it changes with age.
A longitudinal study of children and three follow up studies of adults.
Farnborough, Preston, and Hertfordshire, England, and a national sample in Britain.
1895 children aged 0-10 years, 3240 men and women aged 36 years, 459 men and women aged 46-54 years, and 1231 men and women aged 59-71 years. The birth weight of all subjects had been recorded.
Systolic blood pressure.
At all ages beyond infancy people who had lower birth weight had higher systolic blood pressure. Systolic blood pressure was not related to growth during infancy independently of birth weight. The relation between systolic pressure and birth weight became larger with increasing age so that, after current body mass was allowed for, systolic pressure at ages 64-71 years decreased by 5.2 mm Hg (95% confidence interval 1.8 to 8.6) for every kg increase in birth weight.
Essential hypertension is initiated in fetal life. A raised blood pressure is then amplified from infancy to old age, perhaps by a positive feedback mechanism.
Hypertension in the rat has been demonstrated to be determined in utero by exposure to maternal low-protein diets. Assessment was made of the response of rats with maternal diet-induced hypertension to a chronic high intake of sodium chloride. Normotensive and hypertensive animals were provided with either drinking water (control) or 1.5% sodium chloride over a 7-day period. Normotensive rats significantly increased blood pressure in response to the increased salt intake. 5-7 days after the start of the study systolic blood pressure was 30-41 mm Hg higher than in controls. 7 days of salt drinking did not alter blood pressure in maternal low-protein diet-exposed, hypertensive rats. In both normotensive and hypertensive groups provision of 1.5% sodium chloride significantly increased fluid intake. In hypertensive rats in the increased fluid intake appeared to be an immediate response, whilst normotensive rats increased intake only after the first day. Urinary volume was increased in both groups of animals receiving salt, within 1 day, and Na+ excretion similarly increased by between 3.5- and 4.5-fold in both groups. K+ excretion initially decreased significantly in both normotensive and hypertensive rats drinking 1.5% sodium chloride, but returned to pre-salt drinking levels by day 5 of the experiment. Rats with maternal-diet-induced hypertension appear to be insensitive to the hypertensive effects of sodium chloride. This insensitivity does not appear to stem from a more rapid clearance of excess sodium, and may relate to other aspects of kidney function and metabolism.
Low birth weight has been associated with an increased risk of hypertension, and high birth weight has been associated with increased adult body mass index. Published studies on adults have included only a small number of women.
We studied 71 100 women in the Nurses Health Study I (NHS I) who were 30 to 55 years of age in 1976 and 92 940 women in the Nurses' Health Study II (NHS II) who were 25 to 42 years of age in 1989. Information on birth weight, blood pressure, physician-diagnosed hypertension, and other relevant variables was collected by biennial mailed questionnaire. Ninety-five percent of the women were white. Compared with women in the middle category of birth weight (NHS I, 7.1 to 8.5 lb; NHS II, 7.0 to 8.4 lb), the age-adjusted odds ratio of hypertension in NHS I women with birth weights < 5.0 lb was 1.39 (95% CI, 1.29 to 1.50); in NHS II, for birth weights < 5.5 lb, the age-adjusted odds ratio was 1.43 (95% CI, 1.31 to 1.56). There was no material change in the estimates after adjustment for other risk factors. In addition, compared with women in NHS I who weighed 7.1 to 8.5 lb at birth, those who weighed > 10 lb had an age-adjusted odds ratio of 1.62 (95% CI, 1.38 to 1.90) of being in the highest (> 29.2 kg/m2) versus the lowest (< 21.9 kg/ m2) quintile of body mass index in midlife. Similar results were seen in the NHS II cohort.
Early life exposures affecting birth weight may be important in the development of hypertension and obesity in adults.
Coronary heart disease is predicted to become the commonest cause of death in india within 15 years People from India living overseas already have high rates of the disease that are not explained by known coronary risk factors. Small size at birth is a newly described risk factor for coronary heart disease, but associations between size at birth and the disease have not been examined in India.
We studied 517 men and women who were born between 1934 and 1954 in a mission hospital in Mysore, South India, and who still lived near to the hospital. We related the prevalence of coronary heart disease, defined by standard criteria, to their birth size.
25 (9%) men and 27 (11%) women had coronary heart disease. Low birthweight, short birth length, and small head circumference at birth were associated with a raised prevalence of the disease. Prevalence fell from 11% in people whose birthweights were 5.5 lb (2.5 kg) or less to 3% in those whose birthweights were more than 7 lb (3.1 kg), p for trend = 0.09. The trends were stronger and statistically significant among people aged 45 years and over (p = 0.03 for birthweight, 0.04 for length, and 0.02 for head circumference). High rates of disease were also found in those whose mothers had a low body weight during pregnancy. The highest prevalence of the disease (20%) was in people who weighted 5.5 lb (2.5 kg) or less at birth and whose mothers weighted less than 100 lb (45 kg) in pregnancy. These associations were largely independent of known coronary risk factors.
In India, as in the UK, coronary heart disease is associated with small size at birth, suggesting that its pathogenesis is influenced by events in utero. The association with low maternal bodyweight is further evidence that the disease originates through fetal undernutrition. Prevention of the rising epidemic of the disease in India may require improvements in the nutrition and health of young women.
1. In the rat, hypertension is induced by fetal exposure to maternal low-protein diets. The effect on blood pressure of undernutrition before conception and during discrete periods in early, mid or late pregnancy was assessed using an 18% casein (control) diet and a 9% casein diet to apply mild protein restriction.
2. The offspring of rats fed 9% casein developed raised blood pressure by weaning age. Feeding a low-protein diet before conception was not a prerequisite for programming of hypertension.
3. Hypertension was observed in rats exposed to low protein during the following gestational periods: days 0–7, days 8–14 and days 15–22. Blood pressure increases elicited by these discrete periods of undernutrition were lower than those induced by feeding a low-protein diet throughout pregnancy. The effect in early gestation was significant only in male animals. Post-natal growth of male rats exposed to low-protein diets was accelerated, but kidneys were small in relation to body weight.
4. Biochemical indices of glucocorticoid action in liver, hippocampus, hypothalamus and lung were elevated in rats exposed to low-protein diets in utero. The apparent hypersensitivity to glucocorticoids was primarily associated with undernutrition in mid to late gestation.
5. Plasma renin activity was elevated in rats exposed to 9% casein over days 15–22 of gestation. Animals undernourished over days 0–7 and 8–14 produced pups with lower plasma angiotensin II concentrations at weaning.
6. Fetal exposure to maternal low-protein diets for any period in gestation may programme hypertension in the rat. Alterations to renal structure, renal hormone action or the hypothalamic—pituitary-adrenal axis may all play a role in the programming phenomenon, either independently or in concert.
Low birth weight has been associated with several chronic diseases in adults, including hypertension, diabetes mellitus, and obesity. Further study of these diseases in a large cohort with information on a wide variety of risk factors is essential to determine more precisely the risks associated with birth weight.
We examined the relation between birth weight and cumulative incidence of adult hypertension, incidence of non-insulin-dependent diabetes mellitus, and prevalence of obesity in a cohort of 22,846 US men (Health Professionals Follow-up Study). Birth weights, medical histories, family histories, and other factors were collected by biennial mailed questionnaires. Logistic regression was used to examine the association between birth weight and these chronic adult diseases. Low birth weight was associated with an increased risk of hypertension and diabetes; high birth weight was associated with an increased risk of obesity. Compared with men in the referent birth weight category (7.0 to 8.4 lb), men who weighed < 5.5 lb had an age-adjusted odds ratio for hypertension of 1.26 (95% confidence interval [CI], 1.11 to 1.44) and for diabetes mellitus of 1.75 (95% CI, 1.21 to 2.54). There was no material change after controlling for adult body mass index and parental histories of hypertension and diabetes mellitus. Compared with men in the referent group, the age-adjusted odds ratio of being in the highest versus the lowest quintile of adult body mass index for men with birth weight > or = 10.0 lb was 2.08 (95% CI, 1.73 to 2.50).
These findings support the hypothesis that early life exposures, for which birth weight is a marker, are associated with several chronic diseases in adulthood.
ANG II is known to be important in normal renal development, but the long-term consequences of a suppressed renin-angiotensin system (RAS) during the developmental period are not completely understood. This study tested the hypothesis that the RAS in the developing animal is important in long-term regulation of renal function and arterial pressure. Newborn Sprague-Dawley rat pups were given the ANG II AT1 receptor antagonist losartan (25 mg . kg-1 . day-1 sc) for the first 12 days of postnatal life (Los). Body weights at weaning (22 days) were significantly reduced in Los (53.4 +/- 3.2 vs. 64.5 +/- 3.6 g in controls); however, at the time of study (approximately 22 wk), body weights and the kidney-to-body weight ratios were not different. In chronically instrumented conscious animals, glomerular filtration rate and effective renal plasma flow were reduced by 27 and 20%, respectively, in Los; the filtration fraction was not different. Maximal urine concentrating ability was also reduced in Los (1,351 +/- 45 vs. 2,393 +/- 52 mosmol/kg in controls). Mean arterial pressure was significantly higher in Los (134 +/- 3 vs. 120 +/- 1 mmHg). The number of glomeruli per kidney was reduced by 42% in Los, but the total glomerular volume was unchanged. Thus perinatal blockade of ANG II AT1 receptors results in fewer but enlarged glomeruli, reduced renal function, and an increased arterial pressure in adulthood. These data indicate that perinatal ANG II, acting via AT1 receptors, plays an important role in renal development and long-term control of renal function and arterial pressure. Physiological conditions that cause suppression of the RAS in the developing animal may have long-term consequences for renal function and blood pressure.
This study was designed to test the hypothesis that a reduced number of nephrons from birth leads to increased arterial pressure in adulthood. Newborn Sprague-Dawley rat pups were uninephrectomized during the first 24 h after birth. In chronically instrumented adult animals (approximately 22 wk), mean arterial pressure on a normal (0.20%)-Na+ diet was higher in uninephrectomized rats (133 +/- 2 mmHg vs. 121 +/- 2 mmHg in controls, P < 0.0001). Body weights were not significantly different, but the total kidney-to-body weight ratio was significantly reduced by 14% in adult uninephrectomized animals (P < 0.05). Glomerular filtration rate was reduced by approximately 30% in uninephrectomized rats (1.84 +/- 0.09 vs. 2.63 +/- 0.14 ml/min, P < 0.0002), and effective renal plasma flow was reduced to a lesser degree (6.37 +/- 0.38 vs. 7.87 +/- 0.51 ml/min, P < 0.03), such that the filtration fraction was also reduced (0.291 +/- 0.007 vs. 0.338 +/- 0.014, P < 0.01). After 7-10 days on a high (3.15%)-Na+ diet, arterial pressure increased more in uninephrectomized animals than in controls (20 +/- 3 vs. 1 +/- 1 mmHg, P < 0.003). Thus surgical removal of 50% of the nephrons, when done during development, caused reduced renal function and a salt-sensitive hypertension in adulthood. These data suggest that a reduced nephron endowment from birth, caused by genetic and/or perinatal environmental factors, could contribute to essential hypertension in adulthood.
The objective of this study was to determine whether maternal nutrition and fetal and placental size program blood pressure. A longitudinal study linking the maternal anthropometric measurements of the first antenatal visit, ultrasound data of placental and fetal size, anthropometry at birth, and childhood growth and blood pressure was performed. The subjects were 428 women who attended the antenatal clinic at the University Hospital of the West Indies, Kingston, Jamaica, and their children, who were subsequently followed up. Systolic blood pressure at ages 1, 2, 2.5, 3, and 3.5 years was the main outcome measure. Pooling the data across ages, systolic blood pressure fell by 1.4 mm Hg for every 1-kg increase in birth weight (95% CI 0.2 to 2.7, P=0.02) and by 1.2 mm Hg for every 100-mL increase in placental volume at 20 weeks of gestation (95% CI 0.4 to 2.0, P=0.004). Blood pressure was also negatively associated with placental volume at 17 weeks and fetal abdominal circumference at 20 weeks. Measures of maternal nutritional status were strongly related to birth weight and placental volume but not directly to childhood blood pressure at these young ages. In conclusion, blood pressure is associated with fetal size in this population, as previously described among Europeans. We found associations between placental volume and abdominal circumference in the second trimester and childhood blood pressure, suggesting that the initiating events of blood pressure programming occur early in pregnancy. Measures of maternal nutritional status were not directly related to childhood blood pressure at these young ages but were strong predictors of both birth weight and placental volume, suggesting an indirect relation.
Epidemiological studies have suggested that low birthweight is a risk factor for the development of essential hypertension in adulthood, but the mechanism is unknown.
A rat model of intrauterine growth retardation was employed. Pregnant Sprague-Dawley rats were kept on 6% protein or on control isocaloric 20% protein diet from gestational day 12 until term. Systolic blood pressures of the offspring were monitored by the tail cuff method. Apoptosis was determined by the TUNEL method, cell proliferation by anti-Ki67 antibody, and the total number of glomeruli by the maceration method. Results are mean +/- SD.
The kidney and body sizes of the offspring from the low-protein pregnancies (LP) were proportionately decreased at birth. Full catch-up growth occurred during the first two weeks of life. The kidneys were normal by standard histology but exhibited increased apoptosis without increased cell proliferation at eight weeks of age. The total number of glomeruli per kidney was decreased by 28% in males (P < 0.001) and by 29% in females (P < 0.01). By eight weeks of age, both male and female LP had systolic blood pressures that were 20 to 25 mm Hg higher than those of control animals (P < 0.001), and their 18-month survival was significantly decreased (44 vs. 93%, P < 0.01). During the prehypertensive stage, at four weeks of age, PRA in LP was low (1.7 +/- 1.4 vs. 19.7 +/- 5.5 ng/mL/hour in males, P < 0.0001; 4.9 +/- 2.2 vs. 14.9 +/- 7.2 ng/mL/hour in females, P < 0.0005), and aldosterone was high (93 +/- 15 vs. 54 +/- 27 pg/mL in males, P < 0. 005; 93 +/- 20 vs. 48 +/- 20 pg/mL in females, P < 0.0001). Smaller but significant differences persisted at eight weeks of age.
Adult blood pressure profile is susceptible to prenatal programming by maternal low-protein diet in the rat. The mechanism may involve an altered renin-aldosterone axis and a deficit in total nephron number.
Restriction of maternal protein intake during rat pregnancy produces offspring that are hypertensive in adulthood, but the mechanisms are not well understood. Our purpose was to determine whether this adult hypertension could be programmed during development by suppression of the fetal/newborn renin-angiotensin system (RAS) and a consequent reduction in nephron number. Pregnant rats were fed a normal protein (19%, NP) or low-protein (8.5%, LP) diet throughout gestation. Birth weight was reduced by 13% (p < 0.0005), and the kidney/body weight ratio was reduced in LP pups. Renal renin mRNA levels were significantly reduced in newborn LP pups; renal renin concentration and renin immunostaining were suppressed. Renal tissue angiotensin II levels were also suppressed in newborn LP (0.079 +/- 0.002 ng/mg, LP versus 0.146 +/- 0.016 ng/mg, NP, p < 0.01). Mean arterial pressure in conscious, chronically instrumented adult offspring (21 wk) was higher in LP (135 +/- 1 mm Hg, LP versus 126 +/- 1 mm Hg, NP, p < 0.00007), and GFR normalized to kidney weight was reduced in LP (p < 0.04). The number of glomeruli per kidney was lower in adult LP offspring (21,567 +/- 1,694, LP versus 28,917 +/- 2,342, NP, p < 0.03), and individual glomerular volume was higher (1.81 +/- 0.16 10(6) microm(3), LP versus 1.11 +/- 0.10 10(6) microm(3), NP, p < 0.005); the total volume of all glomeruli per kidney was not significantly different. Thus, perinatal protein restriction in the rat suppresses the newborn intrarenal RAS and leads to a reduced number of glomeruli, glomerular enlargement, and hypertension in the adult.
Epidemiological surveys have suggested that intrauterine growth retardation is a risk factor for the development of hypertension in later life. A rat model of intrauterine growth retardation, induced by maternal low-protein diet during the second half of pregnancy, was used to study the relationship between birth weight and adult hypertension. The offspring were born at term and were allowed to nurse normally until weaned to standard chow at 4 weeks of age. They had 15% lower birth weights than control offspring, with complete catch-up growth by age 4 weeks. Both females and males developed progressively worsening hypertension beginning at 8 weeks. The 11-month survival rate was 69% versus 100% in control animals. During the early stages of the hypertension, plasma creatinine was normal, plasma sodium concentration was slightly higher than that of control animals, plasma renin activity was suppressed, and the males had mild proteinuria. Renal function remained normal throughout the 11-month observation period, but plasma renin activity gradually rose above control values. Angiotensin-converting enzyme inhibition by enalapril, begun at 8 weeks of age, was effective in completely normalizing the blood pressure, but did not totally prevent the extra mortality. Sprague-Dawley and Wistar rat strains developed equally severe hypertension after maternal protein deprivation, despite their different susceptibilities to nephrosclerosis with aging. In conclusion, maternal low-protein diet resulted in low birth weight and adult hypertension in the rat. Primary sodium retention and expanded extracellular volume may be critical factors during the development of the hypertension.
The present study was designed to determine whether adult hypertension caused by a reduced number of nephrons from birth is due to preceding glomerular damage. Newborn male Sprague-Dawley rat pups were uninephrectomized during the first 24 hours after birth (UNX rats). At 20 weeks of age, chronically instrumented UNX animals were hypertensive on a normal-sodium (0.20%) diet compared with sham-operated controls (142+/-2 versus 124+/-2 mm Hg in controls). Body weights and the total kidney-to-body weight ratio were not significantly different in adult UNX animals compared with controls. Glomerular filtration rate (GFR) was reduced by 49% in UNX rats (1.85+/-0.24 versus 3.65+/-0.22 mL/min). Urine protein excretions were higher in UNX rats (20+/-2 versus 7+/-1 mg/d in controls). On a high-sodium (3.15%) diet, arterial pressure increased more in UNX than in controls (28+/-9 versus 3+/-1 mm Hg). In contrast, in animals studied at 8 weeks of age, GFR was only reduced by 26% in UNX animals (2.02+/-0.06 versus 2.73+/-0.07 mL/min). Their hypertension (125+/-2 versus 117+/-2 mm Hg) was also salt sensitive (increase on high-sodium diet of 35+/-11 versus 8+/-2 mm Hg in controls) but was not associated with proteinuria or histological signs of glomerular disease. Number of glomeruli per kidney in UNX animals was not different from controls, but individual glomerular volume increased by 41%. Thus, surgical removal of 50% of the nephrons, when done during development, causes reduced renal function and salt-sensitive hypertension in adulthood. Hypertension is present earlier in life than signs of glomerular disease, which suggests that hypertension is a major contributor to rather than primarily resulting from onset of renal disease.
A diminished number of nephrons has been proposed as one of the factors contributing to the development of primary hypertension.
To test this hypothesis, we used a three-dimensional stereologic method to compare the number and volume of glomeruli in 10 middle-aged white patients (age range, 35 to 59 years) with a history of primary hypertension or left ventricular hypertrophy (or both) and renal arteriolar lesions with the number and volume in 10 normotensive subjects matched for sex, age, height, and weight. All 20 subjects had died in accidents.
Patients with hypertension had significantly fewer glomeruli per kidney than matched normotensive controls (median, 702,379 vs. 1,429,200). Patients with hypertension also had a significantly greater glomerular volume than did the controls (median, 6.50x10(-3) mm3 vs. 2.79x10(-3) mm3; P<0.001) but very few obsolescent glomeruli.
The data support the hypothesis that the number of nephrons is reduced in white patients with primary hypertension.
- Weeks Woods Ll
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WOODS LL, WEEKS DA, RASCH R: Hypertension after neonatal
uninephrectomy in rats precedes glomerular damage. Hypertension
38:337-342, 2001
Effect of normal development on compensatory renal growth
- Larsson
Birth weight and adult hypertension, diabetes mellitus, and obesity in US men
- Curhan
Fetal and placental size and risk of hypertension in adult life
- Barker