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Renin-angiotensin system and bradykinin pathways. Angiotensinogen is a precursor of angiotensin produced by the liver. Renin, an enzyme produced by the juxtaglomerular cells of the kidney, catalyzes the first step in the activation pathway of angiotensinogen to angiotensin I. ACE (angiotensin I-converting enzyme), mainly produced by the lungs and kidney, plays a pivotal role by hydrolyzing angiotensin I into angiotensin II. This product interacts with angiotensin II receptors, leading to potent vasoconstriction, release of aldosterone by the adrenal cortex, ADH (antidiuretic hormone) secretion by the pituitary gland, renal sodium and fluid retention, sympathetic overdrive, and thirst. There are two distinct subtypes of cell surface receptors, angiotensin receptors types 1 and 2 (AT1 and AT2). AT1 seems to mediate the major cardiovascular effects of angiotensin II. In pathologic conditions, RAS is hyperactive, leading to hypertension and kidney lesions in a "vicious cycle". In the bradykinin system, kininogens are multifunctional proteins synthesized in the liver that circulate in the plasma and other body fluids. The tissue kallikrein is synthesized in the cells as a precursor and converted into an active form by the cleavage of an amino terminal peptide. The enzymatic action of kallikreins on kininogens generates bradykinin that interacts with bradykinin receptors and elicits numerous responses, including vasodilatation, edema, smooth muscle spasm, and stimulation of pain fibers. The kininases, such as ACE, are present in the plasma, endothelial cells, and in the tissues to regulate the physiological functions of the kinins in the body.
Source publication
About 80% of CKD (chronic kidney disease) patients are hypertensive, and kidney function and blood pressure are clearly related to both physiologic and pathologic conditions in a "vicious cycle". In this pathologic scenario, there is a renin-angiotensin system (RAS) hyperactivity associated to progression of renal damage. Current guidelines indicat...
Contexts in source publication
Context 1
... produced by the juxtaglomerular cells of the kidney, is encoded by the REN gene located on chromosome 1q32. Renin occurs in organs other than the kidney, e.g., in the brain, where it is implicated in the regulation of numerous activities. The enzyme which catalyzes the first step in the activation pathway of angiotensinogen to angiotensin I ( Fig. 1) and its gene mutation have been associated with hyperproreninemia, hyperuricemic nephropathy, and renal tubular dysgenesis (OMIM 179820) (14 ...
Context 2
... a precursor of angiotensin and encoded by the AGT gene located on chromosome 1q42 -q43, is mainly produced by the liver and found in the α2-globulin fraction of plasma. In the RAS, angiotensinogen is cleaved by renin (Fig. 1) and AGT mutations were related to renal tubular dysgenesis, susceptibility to essential hypertension, and preeclampsia (OMIM 106150) (17 -19). A meta-analysis performed by our group analyzing data involving 26,818 subjects from 46 . Renin-angiotensin system and bradykinin pathways. Angiotensinogen is a precursor of angiotensin produced ...
Context 3
... 17q23.3, whereas the ACE2 gene is located on chromosome Xp22 and it may counteract some of the effects of ACE (21). ACE is mainly produced by the lungs and plays a pivotal role in the RAS by hydrolyzing angiotensin I into angiotensin II. This product is a potent vasopressor and it acts on the adrenal cortex causing the release of aldosterone (Fig. 1). In addition, ACE is also able to inactivate bradykinin-a potent vasodilator (15,22,23). ACE genetic variants have been associated with renal tubular dysgenesis, microvascular complications of diabetes, progression of a severe acute respiratory syndrome, and the susceptibility to myocardial infarction and Alzheimer's disease (OMIM ...
Context 4
... and AT2), interact with angiotensin II. AGTR1 and AGTR2 genes are located on chromosomes 3q21 -q25 and Xq21 -23, respectively. AT1 seems to mediate the major cardiovascular effects of angiotensin II, leading to effects such as vasoconstriction, increased arterial blood pressure, increased myocardial contractility, and sodium and water retention ( Fig. 1) (12, 15, 23, 31 -33). Some AGTR1 variants were associated with susceptibility to essential hypertension and renal tubular dysgenesis (OMIM 106165) ...
Context 5
... responses, including vasodilatation, edema, smooth muscle spasm, and stimulation of pain fibers. The kininases, kinin-inactivating enzymes (such as kininase I, kininase II, or angiotensin-converting enzyme), are present in the plasma, endothelial cells, and in different tissues to regulate the physiological functions of the kinins in the body (Fig. 1) (36,37). The BDKRB2 9 pb insertion/deletion (I/D) polymorphism has been found to affect the transcription of the gene in a cis-acting manner and has been associated with several cardiovascular related phenotypes (OMIM 113503) ...
Similar publications
This study investigated the action of angiotensin 1–7 (Ang (1–7)) on renal haemodynamic and excretory function in the two‐kidney one‐clip (2K1C) and deoxycorticosterone acetate (DOCA)‐salt rat models of hypertension, in which the endogenous renin–angiotensin system (RAS) activity was likely to be raised or lowered, respectively. Rats were anaesthet...
Citations
... 37 Tomatoes contain a significant amount of lycopene, and it is the most studied tomato component. 6 Lycopene not only inhibits the angiotensin-converting enzyme and its gene expression, thus blocking the production of angiotensin II, a vasoconstrictor that increases BP, 38 but can also indirectly increase nitric oxide generation in the endothelium. 11 Lower levels of nitric oxide, through reactive oxygen species, induce oxidative stress causing changes in the structure of blood vessels, 38 increasing vascular growth, migration, 38 and leading to endothelial dysfunction and thrombotic activity by inhibiting platelet adhesion and aggregation. ...
... 6 Lycopene not only inhibits the angiotensin-converting enzyme and its gene expression, thus blocking the production of angiotensin II, a vasoconstrictor that increases BP, 38 but can also indirectly increase nitric oxide generation in the endothelium. 11 Lower levels of nitric oxide, through reactive oxygen species, induce oxidative stress causing changes in the structure of blood vessels, 38 increasing vascular growth, migration, 38 and leading to endothelial dysfunction and thrombotic activity by inhibiting platelet adhesion and aggregation. 11 Bioactive tomato compounds have also demonstrated protective action against inflammation caused by certain chemical mutagens (lipopolysaccharide, hydrogen peroxide, and methyl methanesulphonate), suppressing proinflammatory molecules such as interleukins, TNF-a, cyclooxygenase, and NF-κB. ...
... 6 Lycopene not only inhibits the angiotensin-converting enzyme and its gene expression, thus blocking the production of angiotensin II, a vasoconstrictor that increases BP, 38 but can also indirectly increase nitric oxide generation in the endothelium. 11 Lower levels of nitric oxide, through reactive oxygen species, induce oxidative stress causing changes in the structure of blood vessels, 38 increasing vascular growth, migration, 38 and leading to endothelial dysfunction and thrombotic activity by inhibiting platelet adhesion and aggregation. 11 Bioactive tomato compounds have also demonstrated protective action against inflammation caused by certain chemical mutagens (lipopolysaccharide, hydrogen peroxide, and methyl methanesulphonate), suppressing proinflammatory molecules such as interleukins, TNF-a, cyclooxygenase, and NF-κB. ...
Aims
Clinical studies have produced conflicting evidence on the effects of the consumption of tomatoes on blood pressure, and there are limited data from epidemiologic studies. This study assesses whether tomato consumption (Solanum lycopersicum L.) is associated with Systolic (SBP) and Diastolic Blood Pressure (DBP), and the risk of hypertension in a prospective 3-year longitudinal study in older adults at high cardiovascular risk.
Methods
The present study was carried out within the PREDIMED (Prevención con Dieta Mediterránea) trial involving 7,056 (82.5% hypertensive) participants. The consumption of tomato (g/d) was measured using a validated Food Frequency Questionnaire (FFQ) and categorized into 4 groups: lowest (<44 g), intermediate (44-82 g), upper-intermediate (82 -110 g), and highest (>110 g). Multilevel linear mixed models examined blood pressure and tomato consumption association. Cox proportional-hazards models analyzed hypertension risk in 1,097 non-hypertensive participants, studying risk reductions versus the lowest tomato consumers.
Results
An inverse association between tomato consumption and diastolic blood pressure was observed between the intermediate group β = -0.65 mmHg [95% CI:-1.20, -0.10] and the lowest consumption group. A significant inverse association was observed for blood pressure in grade 1 hypertension participants in the intermediate tomato consumption group. The risk of hypertension decreased with consumption of >110 g/d tomato (highest vs lowest consumption; HR, 0.64 [95% CI, 0.51–0.89]).
Conclusions
Tomato consumption, including tomato-based products, is beneficial in preventing and managing hypertension. Higher tomato intake reduces hypertension risk by 36%, and moderate consumption lowers blood pressure, especially in grade 1 hypertension.
... In a classical pathway, angiotensin (Ang) II produced from Ang I with the help of angiotensin-converting enzyme (64). In physiological conditions, Ang II binds to its own receptor in the adrenal cortex, causing the release of aldosterone and sodium reabsorption in the kidneys (65). Also, the Ang (1-7)/ACE2 cascade is known as the non-classic RAS (66). ...
: The “Cardiorenal Syndrome (CRS) “includes a simultaneous heart-kidney dysfunction in such a way that damage in one organ subsequently leads to damage in another and vice versa. Although for the first time in a classification in 2008, two main groups called cardiorenal and reno-cardiac (based on the onset of the disease in each organ) were used for this term, but today there are five main classifications for it. Various factors take part in this syndrome pathophysiology, including endotoxemia, inflammatory processes, metabolic derangements, infections, imbalance in neurohormones secretion, venous congestion and immunological dysfunction. But the main cause of this syndrome' onset in many cases is over-activity of renal sympathetic nerves and subsequently increased interaction with the stimulated renin-angiotensin system (both classical and non-classical axes). Regarding this fact, today renal denervation is known as a useful therapeutic approach in solving the disorders of this syndrome, which its safety and efficacy have been proven in many experimental and clinical studies. Respecting the above information, the aim of this study is to investigate the therapeutic effects of renal denervation in solving CRS disorders in more details, relying on the results of experimental and human studies in this field. The effects of using renin angiotensin blockers and other treatment methods for this syndrome have also been mentioned.
... Historically, RAS has been widely acknowledged as a vital system for humoral regulation in the human body. It comprises several peptide hormones and related enzymes [82]. The following molecules are involved in the conventional RAS: angiotensin I (Ang I), angiotensin II (Ang II), angiotensin I-converting enzyme (ACE), angiotensin I-converting enzyme-2 (ACE2), angiotensinogen, renin, aldosterone, Ang II type 1 receptor (AT1R), and Ang II type 2 receptor (AT2R). ...
Diabetic nephropathy (DN) is an enduring condition that leads to inflammation and affects a substantial number of individuals with diabetes worldwide. A gradual reduction in glomerular filtration and emergence of proteins in the urine are typical aspects of DN, ultimately resulting in renal failure. Mounting evidence suggests that immunological and inflammatory factors are crucial for the development of DN. Therefore, the activation of innate immunity by resident renal and immune cells is critical for initiating and perpetuating inflammation. Toll-like receptors (TLRs) are an important group of receptors that identify patterns and activate immune responses and inflammation. Meanwhile, inflammatory responses in the liver, pancreatic islets, and kidneys involve inflammasomes and chemokines that generate pro-inflammatory cytokines. Moreover, the activation of the complement cascade can be triggered by glycated proteins. This review highlights recent findings elucidating how the innate immune system contributes to tissue fibrosis and organ dysfunction, ultimately leading to renal failure. This review also discusses innovative approaches that can be utilized to modulate the innate immune responses in DN for therapeutic purposes.
... High blood pressure is another disease associated with chronic kidney disease (CKD), whose prevalence ranges from 60% to 90% depending on the stage and cause of CKD (Stec, Hosick, and Joey 2012). Studies in the USA show hypertension as a leading cause of end-stage renal disease and is associated with a high risk of cardiovascular morbidity and mortality (Caleb et al. 2012). ...
Abstract
Background: Chronic kidney disease is one of the most serious public health burdens globally, with significant morbidity, mortality, and reduced patient life expectancy. Many sub-Saharan African countries face double-burden challenges in the treatment of chronic kidney disease and its complications. This study aims to evaluate serum uric acid and its correlation with estimated glomerular filtration rate, as well as other risk factors among chronic kidney disease patients on follow-up at Jimma University specialised referral hospital.
Method: A hospital-based cross-sectional study was conducted at Jimma University Medical Centre from August 6, 2022, to November 13, 2022. Using a consecutive sampling technique, a total of 140 CKD follow-up patients were recruited into the current study. Data were collected using interviewer-based structured questionnaires, record reviews, and physical examinations. The collected data were analysed by SPSS version 25.0. The correlation between eGFR and uric acid concentrations was examined by Pearson’s correlation analyses. Univariate and multivariate linear regression were used to test predictors of serum uric acid in the study participants.
Result: A total of 140 study participants were recruited for this study. Subjects included (54.3% [n=76]) men and (45.7% [n=64]) women, respectively. The mean (SD) age of the study subjects was 51.04±9.02 years. The mean value of serum uric acid was 7.2±2.1mg/dl, whereas the mean of estimated glomerular filtration rate (eGFR) was 54.2±31 mL/min/1.73m2. Furthermore, the mean values of serum creatinine and blood urea nitrogen among participants in this study were 3.2±1.4 and 67.8±35.8 mg/dL. In the current study, estimated glomerular filtration rate (eGFR) value was negatively correlated (r=-0.912, P<0.001) with uric acid. However, systolic blood pressure was positively correlated (r=0.584, P<0.001) with uric acid. Moreover, the eGFR value was negatively associated (β=-0.060, P=<0.001) with uric acid among study participants.
Conclusion: Based on the current study findings, an increase in serum uric acid was associated with a decrease in eGFR value. Increased serum uric acid, increased body mass index (BMI) and high blood pressure are independent risk factors for disease progression in patients with CKD
... Excess sodium and fluid retention in CKD may trigger autoregulation. In response to excessive blood flow, tissue arterioles vasoconstrict and increase peripheral vascular resistance, activating the renin-angiotensin-aldosterone system, leading to disruption in the regulation of blood pressure [60][61][62] . ...
Seizures are not uncommon in patients with chronic kidney disease (CKD), with an approximate incidence of roughly 10%. There are two primary groups: Patients who develop acute provoked seizures in the setting of CKD and patients with pre-existing epilepsy who then develop CKD. The recognition of potential etiology and management of seizures in this patient population may be challenging for clinicians, particularly non-neurologists. Standard antiepileptic drug (AED) treatment is indicated for those with pre-existing epilepsy. The prescription of AED in CKD population requires careful consideration, due to potentially altered pharmacokinetics. Clinicians frequently encounter challenges in the selection, loading, titration, and maintenance of AEDs. There are few internationally recognized consensus recommendations for AED prescription in CKD and dialysis. Non-AED management aims at addressing factors that may have provoked the seizure. In this article, we provide an in-depth review of the potential etiologies and pathophysiological pathways of provoked seizures in CKD. We discuss strategies, including non-AED treatment options, which aim to prevent, and/or manage provoked seizures in the setting of CKD. We discuss the AEDs used in contemporary clinical practice and how their metabolism is affected by CKD, concurrent AED prescriptions, and dialysis.
... The renin-angiotensin-aldosterone system (RAAS) maintains blood pressure by regulating sodium, potassium, and fluid volume. Dysregulation of the renin-angiotensin-aldosterone system leads to the development of chronic hypertension (Santos et al., 2012;Carey, 2015;Te Riet et al., 2015). Activation of renin-angiotensinaldosterone system occurs when the precursor, prorenin, is converted to renin by the juxtaglomerular cells of the kidney (Hsueh & Baxter, 1991;von Lutterotti et al., 1994). ...
Preeclampsia is a pregnancy-specific condition and a leading cause of maternal and fetal morbidity and mortality. It is thought to occur due to abnormal placental development or dysfunction, because the only known cure is delivery of the placenta. Several clinical risk factors are associated with an increased incidence of preeclampsia including chronic hypertension, diabetes, autoimmune conditions, kidney disease, and obesity. How these comorbidities intersect with preeclamptic etiology, however, is not well understood. This may be due to the limited number of animal models as well as the paucity of studies investigating the impact of these comorbidities. This review examines the current mouse models of chronic hypertension, pregestational diabetes, and obesity that subsequently develop preeclampsia-like symptoms and discusses how closely these models recapitulate the human condition. Finally, we propose an avenue to expand the development of mouse models of preeclampsia superimposed on chronic comorbidities to provide a strong foundation needed for preclinical testing.
... Hypertension is a feature of about 80% of CKD patients, and the current guidelines indicate the pharmacologic blockade of the RAAS as the first choice of antihypertensive intervention. However, both response to treatment and renal protection show significant inter-individual variability (Santos et al., 2012). The variability may arise due to varying levels of ACE in plasma and tissue being partly determined by a genetic polymorphism. ...
Chronic kidney disease presents a health challenge that has a complex underlying pathophysiology, both acquired and inherited. The pharmacotherapeutic treatment options available today lower the progression of the disease and improve the quality of life but cannot completely cure it. This poses a challenge to the healthcare provider to choose, from the available options, the best way to manage the disease as per the presentation of the patient. As of now, the recommended first line of treatment to control the blood pressure in chronic kidney disease is the administration of renin–angiotensin–aldosterone system modulators. These are represented mainly by the direct renin inhibitor, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers. These modulators are varied in their structure and mechanisms of action, hence showing varying treatment outcomes. The choice of administration of these modulators is determined by the presentation and the co-morbidities of the patient, the availability and affordability of the treatment option, and the expertise of the healthcare provider. A direct head-to-head comparison between these significant renin–angiotensin–aldosterone system modulators is lacking, which can benefit healthcare providers and researchers. In this review, a comparison has been drawn between the direct renin inhibitor (aliskiren), angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers. This can be of significance for healthcare providers and researchers to find the particular loci of interest, either in structure or mechanism, and to intervene as per the case presentation to obtain the best possible treatment option.
... Key player of RAAS is the liver-derived β 2 -globuline angiotensinogen that is processed in two steps to become the operational angiotensin II (ATII). First, the protease renin, released by the juxtaglomerular apparatus of the kidney, catalyzes the conversion of angiotensinogen into the decapeptide angiotensin I. Second, the angiotensin converting enzyme (ACE), a single-pass transmembrane protein expressed ubiquitously by endothelial cells with pronounced expression in the pulmonary and renal vasculature, cleaves angiotensin I (ATI) to form the octapeptide ATII [15]. ATII operates via two G protein-coupled receptors, the angiotensin II receptor type 1 (AT1R) and the angiotensin II receptor type 2 (AT2R). ...
Background/aims:
Hypertension is treated primarily with angiotensin II (ATII) receptor blockers (ARBs) and angiotensin converting enzyme (ACE) inhibitors (ACEIs). Both ATII and ACEIs can trigger signal transduction via ACE, and a possible correlation between ARB/ACEI therapy and an increased risk of cancer is highly controversial. The question of whether or not ACE as a potential signal transducer affects human melanoma (MV3) cell behavior prompted the present study.
Methods:
Expression of ACE, ATII receptor types 1, 2 (AT1R, AT2R), COX2 and MMP2 in MV3 cells was examined by qPCR. AT1R, AT2R and ACE were inhibited with losartan, EMA401 and lisinopril, respectively. Adhesion, migration and invasiveness of MV3 cells seeded on a hepatocyte (Huh7) monolayer or a reconstituted collagen type I matrix were analyzed using video microscopy and Boyden chambers. Integrity of the Huh7 cell layer was confirmed by measuring transepithelial electrical resistance (TEER). ERK1/2 phosphorylation and MMP2 secretion were evaluated by Western blotting. MMP2 activity was inhibited with ARP-100.
Results:
Losartan, EMA401 and lisinopril stimulated MV3 melanoma cell migration and invasion in a coculture model with Huh7 cells while leaving proliferation and adhesion largely unaffected. The drugs did not interfere with TEER of the hepatocyte monolayer nor with MV3 cell proliferation, but tended to increase the phosphorylation of ERK1/2 and the expression of both COX2 and MMP2. Lisinopril caused a significant increase in MV3 cells' MMP2 secretion and an accelerated MV3 cell-mediated TEER breakdown. The MMP2 inhibitor ARP-100 could antagonize the lisinopril-stimulated invasion of the hepatocyte layer.
Conclusion:
Lisinopril stimulates MV3 cell invasion by increasing the expression and secretion of MMP2.
... According to recent studies, hyperglycemia-induced activation of the electron transport chain can increase reactive oxygen species production, which is thought to initiate the development of complications in diabetes (12). In DKD patients, hyperglycemia and hemodynamic alterations, especially activation of the renin-angiotensin system (RAS), trigger various cell signaling cascades, including the MAPK (p38 and JNK) pathways (5,13). In response to these signals, chemokines, growth factors, and profibrotic cytokines produced by renal cells cause the activation of macrophages, resulting in a cycle of inflammation, oxidative stress, cellular injury, progressive fibrosis, and damage to the glomerular filtration rate. ...
... suggest that acrolein plays a crucial role in the pathogenesis of DN, and plasma Acr-PC levels in DKD patients may be a diagnostic marker. RAS activation significantly influences renal disease progression (13). Ang II promotes water and salt retention, oxidative stress, vasoconstriction, inflammation, and fibrosis, contributing to DN (41). ...
Objective
Diabetic nephropathy (DN), also known as diabetic kidney disease (DKD), is a major chronic complication of diabetes and is the most frequent cause of kidney failure globally. A better understanding of the pathophysiology of DN would lead to the development of novel therapeutic options. Acrolein, an α,β-unsaturated aldehyde, is a common dietary and environmental pollutant.
Design
The role of acrolein and the potential protective action of acrolein scavengers in DN were investigated using high-fat diet/ streptozotocin-induced DN mice and in vitro DN cellular models.
Methods
Acrolein-conjugated proteins (Acr-PCs) in kidney tissues were examined using immunohistochemistry. Renin-angiotensin system (RAS) and downstream signaling pathways were analyzed using quantitative RT-PCR and Western blot analyses. Acr-PCs in DN patients were analyzed using an established Acr-PC ELISA system.
Results
We found an increase in Acr-PCs in kidney cells using in vivo and in vitro DN models. Hyperglycemia activated the RAS and downstream MAPK pathway, increasing inflammatory cytokines and cellular apoptosis in two human kidney cell lines (HK2 and HEK293). A similar effect was induced by acrolein. Furthermore, acrolein scavengers such as N-acetylcysteine, hydralazine, and carnosine could ameliorate diabetes-induced kidney injury. Clinically, we also found increased Acr-PCs in serum samples or kidney tissues of DKD patients compared to normal volunteers, and the Acr-PCs were negatively correlated with kidney function.
Conclusions
These results together suggest that acrolein plays a role in the pathogenesis of DN and could be a diagnostic marker and effective therapeutic target to ameliorate the development of DN.
... A hormone system reninangiotensin system (RAS) is involved in body fluid regulation but indirectly increases blood pressure [4]. Angiotensinconverting enzymes in the RAS system convert angiotensin Ι to angiotensin ΙΙ, which narrows the blood vessels and causes hypertension [5]. From different natural resources, many ACE-inhibiting peptides have been studied to stabilize blood pressure [6]. ...
The renin-angiotensin system (RAS) is involved in body fluid regulation, but one of its enzymes, angiotensin-converting enzyme (ACE), indirectly causes hypertension by constricting blood vessels. Autoimmune illness is linked to the increased risk of hypertension and cardiovascular disease. In this study, ACE-inhibiting peptides were studied from Artemisia annua proteins. In silico hydrolysis of proteins was performed by BIOPEP-UWM using proteolytic enzymes from plant, microbial, and digestive sources. The physicochemical properties of 1160 peptides were determined using the peptide package of R studio. Di- and tripeptides were mostly released with a molecular weight of 170 to 350 Da. PeptideRanker was used to select 16 peptides from a pool of 1160 peptides based on their likelihood of being bioactive. Molecular docking was performed by DS 2020 and AutoDock Vina, which revealed that the stability of the ligand-receptor complex is due to hydrogen bonding and electrostatic and hydrophobic interactions. Their binding energies ranged from -31.81 to -20.09 kJ/mol. For drug-likeness evaluation, an online tool SwissADME was used that follows the ADME rule (absorption, distribution, metabolism, and excretion) to check the pharmacokinetics and drug-likeness of the compound. In the future, the released peptides can be used to make functional nutraceutical foods against hypertension.
