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Representative figures of glomerular damage. (A) Segmental glomerulosclerosis was observed in a small number of glomeruli in spontaneously hypertensive rats (SHR) (an arrow indicates a representative segmental sclerosis). (B) glomeruli were intact in control Wistar-Kyoto rats (WKY). (C) Spontaneously hypertensive/NIH-corpulent rats [SHR/NDmc-cp (fat/fat)] developed more severe glomerulosclerosis. (D) Glomerular injury was ameliorated in SHR/NDmc-cp (fat/fat) given high-dose olmesartan.
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Prevention or retardation of diabetic nephropathy (DN) includes anti-hypertensive treatment with angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II type 1 receptor blockers (ARB) on the premises that these drugs have an added protective effect beyond their influence on BP. The present study used a strain of spontaneously hypertensiv...
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Context 1
... damage developed mainly in SHR/NDmc-cp (fat/fat) rats (Table 4). At the end of the study, segmental glomerulosclerosis was markedly elevated (P 0.01) in SHR/ NDmc-cp (fat/fat) given the vehicle ( Figure 1C). Olmesartan reduced glomerular damage in a dose-dependent manner (P 0.001). ...
Context 2
... decrease averaged 19 and 48% in the 1 and 5 mg groups, respectively. ( Figure 1D). The fall in glomerular damage observed in the hydralazine group (16%) was similar to that of the low-dose olmesartan group. ...
Context 3
... fall in glomerular damage observed in the hydralazine group (16%) was similar to that of the low-dose olmesartan group. Segmental glomerulosclerosis was present only in a small number of glomeruli in the SHR group ( Figure 1A) and absent in the WKY group ( Figure 1B). ...
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Citations
... Angiotensin II type 1 receptor blocker (ARB) and ACEI are used as major antihypertension drugs worldwide. Both ARB and ACEI reduce AGE formation as metal chelators and antioxidants in vitro [128] and in vivo [129,130]. The effects of anti-AGE accumulation of these drugs were shown in patients with diabetes mellitus [131,132]. ...
Diabetic retinopathy is a tissue-specific neurovascular impairment of the retina in patients with both type 1 and type 2 diabetes. Several pathological factors are involved in the progressive impairment of the interdependence between cells that consist of the neurovascular units (NVUs). The advanced glycation end-products (AGEs) are one of the major pathological factors that cause the impairments of neurovascular coupling in diabetic retinopathy. Although the exact mechanisms for the toxicities of the AGEs in diabetic retinopathy have not been definitively determined, the AGE-receptor of the AGE (RAGE) axis, production of reactive oxygen species, inflammatory reactions, and the activation of the cell death pathways are associated with the impairment of the NVUs in diabetic retinopathy. More specifically, neuronal cell death is an irreversible change that is directly associated with vision reduction in diabetic patients. Thus, neuroprotective therapies must be established for diabetic retinopathy. The AGEs are one of the therapeutic targets to examine to ameliorate the pathological changes in the NVUs in diabetic retinopathy. This review focuses on the basic and pathological findings of AGE-induced neurovascular abnormalities and the potential therapeutic approaches, including the use of anti-glycated drugs to protect the AGE-induced impairments of the NVUs in diabetic retinopathy.
... In another DKD animal model with a strain of spontaneously hypertensive/NIH-corpulent rats, the renal pentosidine content was correlated with the development of proteinuria. Hydralazine not only reduced the renal pentosidine content and attenuated glomerular damage in vivo, but also inhibited the formation of AGE in vitro [29]. Furthermore, we recently showed that hydralazine could protect renal proximal tubular epithelial cells against the insults of high glucose in vitro and prevent the progression of DKD in vivo via antioxidation and anti-inflammation mechanisms, including XO and NADPH oxidase inhibition and nuclear factor erythroid 2-related factor 2/heme oxygenase 1 activation [30]. ...
Hydralazine is a traditional antihypertensive drug that was developed several decades ago. Its most well-known effect is blood pressure lowering by arterial vasodilation. While mainly used an adjunct treatment for clinical hypertension or chronic heart failure, this old drug has also shown potential as a repurposing drug for the atherosclerosis vascular disease and various kidney diseases. Recent experimental studies suggest that hydralazine exerts antioxidative, anti-apoptotic, and HIF-1α stabilization effects for angiogenesis and vascular protection. Hydralazine also exerts reno-protective effects via its antioxidation, DNA demethylation, and anti-inflammation abilities. The above evidence provides advanced rationales for new applications of this drug beyond blood pressure lowering and arterial vasodilation. Here, we summarized the recent experimental advances in the use of hydralazine for either a vascular disease or kidney diseases, or both. Given the wide populations of people with cardiovascular and/or kidney diseases, future studies are worth validating the potential impacts of hydralazine on the clinical outcomes in selected patients.
... (7) The level of AGE in kidney of diabetic nephropathy rats increases in accordance with the level of urinary proteins. (8) Hemoglobin A1c (HbA1c) is an Amadori product that has been measured as a typical marker of glycemic control in diabetes; accurately predicting diabetic complications remains difficult. (9) AGEs are expected to predict the onset of complications and improve the quality of life of patients with lifestylerelated diseases, followed by a reduction in medical expenses. ...
Advanced glycation end products (AGEs), produced by the Maillard reaction between carbohydrates and proteins, may be involved in diabetes and its complications. Accurate quantification of AGEs in vivo can demonstrate the relation between AGEs and pathological conditions, but it is not widely used in clinical practice because of the multiple pretreatment steps before analyses. We developed a fully automated solid-phase extraction system (FSPES) to simplify rate-limiting pretreatment using a cation exchange column. We applied this device to evaluate AGEs in nephropathy. Among the standard samples, we used arginine, lysine, Nε-(carboxymethyl)lysine (CML), Nω-(carboxymethyl)arginine (CMA), Nε-(carboxyethyl)lysine (CEL), and Nδ-(5-hydro-5-methyl-4-imidazolone-2-yl)-ornithine (MG-H1) for FSPES. We analyzed the coefficient of variation (CV) by mass spectrometry. FSPES performed column operations rapidly at a pressure three times higher compared with the conventional method. FSPES stably performed pretreatment. CV results for CML, CMA, CEL, and MG-H1 measurements in bovine and human serum were the same as those in the conventional pretreatment. Among the AGE structures we measured, CML and CEL increased with the decline in kidney function. The CML and CEL levels of patients with nephropathy were significantly higher than those in normal subjects. Thus, FSPES is useful for clarifying the relation between AGEs and various pathological conditions.
... As CML and Lys differ in their structures from furosine only in the furoyl residues (Scheme 1), it could be hypothesized that the furoyl residue of furosine is responsible for these associations. In a type 2 diabetic nephropathy rat model, two anti-hypertensive drugs of different mechanisms of action, i.e., olmesartan and hydralazine, were found to inhibit in vivo formation of protein pentosidine in the kidney and to improve renal damage (Nangaku et al. 2003). Analogous results were observed for various AGEs in vivo Fig. 1 Associations of urinary excretion rates of A CML and B furosine with all-cause mortality in the KTR, and of C CML and D furosine with cardiovascular mortality. ...
Arginine (Arg) and lysine (Lys) moieties of proteins undergo various post-translational modifications (PTM) including enzymatic NG- and Nε-methylation and non-enzymatic NG- and Nε-glycation. In a large cohort of stable kidney transplant recipients (KTR, n = 686), high plasma and low urinary concentrations of asymmetric dimethylarginine (ADMA), an abundant PTM metabolite of Arg, were associated with cardiovascular and all-cause mortality. Thus, the prediction of the same biomarker regarding mortality may depend on the biological sample. In another large cohort of stable KTR (n = 555), higher plasma concentrations of Nε-carboxymethyl-lysine (CML) and Nε-carboxyethyl-lysine (CEL), two advanced glycation end-products (AGEs) of Lys, were associated with higher cardiovascular mortality. Yet, the associations of urinary AGEs with mortality are unknown. In the present study, we measured 24 h urinary excretion of Lys, CML, and furosine in 630 KTR and 41 healthy kidney donors before and after donation. Our result indicate that lower urinary CML and lower furosine excretion rates are associated with higher mortality in KTR, thus resembling the associations of ADMA. Lower furosine excretion rates were also associated with higher cardiovascular mortality. The 24 h urinary excretion rate of amino acids and their metabolites decreased post-donation (varying as little as − 24% for CEL, and as much as − 62% for ADMA). For most amino acids, the excretion rate was lower in KTR than in donors pre-donation [except for S-(1-carboxyethyl)-l-cysteine (CEC) and NG-carboxyethylarginine (CEA)]. Simultaneous GC–MS measurement of free amino acids, their PTM metabolites and AGEs in urine is a non-invasive approach in kidney transplantation.
... Contrarily, it is reported that hyperglycemia along with oxidative stress contributed to the accumulation of pentosidine in rheumatoid arthritis with normoglycemia 32) . The results of our study and previous studies 32,45) showed that hyperglycemia and pentosidine (an AGE) accumulation in tissues does not always occur simultaneously. The exercise regimen alone performed in this study improved hyperglycemia and dyslipidemia; however, it might also enhance RAS activity in the kidney simultaneously. ...
... Conversely, Capt-treatment alone inhibited pentosidine accumulation caused by inhibition of advanced RAS activity in the kidney 16,17) ; however, the dose of Capt (20 mg/kg/ day) 40) administration might have no effect on hyperglycemia. It is believed that the long-term administration of Capt decreases systemic BP, improves renal glomerular hypertension, suppresses mesangial cell and matrix proliferation, and pentosidine deposition in the kidneys through inhibition of RAS activity in the kidney 20, 45,46) . Further examinations are required to elucidate the reason why pentosidine content in the kidney was remarkably reduced despite hyperglycemia observed in the Capt treatment alone group. ...
... The predominant effect of Ang II in the kidney is the constriction of efferent arterioles, which induces an increase in glomerular capillary hydraulic pressure 20, 44) . There are a number of biological mechanisms for glomerular hypertension-induced renal injury, including capillary distension and mesangial cell and matrix proliferation 20, 44,45) . The close association between BP, UAlb/UCr, and renal morphological findings observed after treatment suggests that increased UAlb/UCr, thickened GBM, and expanded A _ (M) observed in the OLETF-Sed and OLETF-Ex groups might be induced by enhanced RAS activity in the kidneys. ...
Our previous studies used type-2 diabetic model Otsuka Long-Evans Tokushima fatty (OLETF) rats, and showed that both exercise and diet regimen decreased body weight (BW) and improved glucose intolerance (GI), and dyslipidemia. However, exercise regimenwas also associated with increased blood pressure (BP), diabetic nephropathy (DN) progression characterized by an increase in urinary albumin excretion (UAlb), and morphological abnormalities of the kidneys. This study examined the effects of an exercise regimen alone and the combined treatment of exercise and an antihypertensive medication, captopril (Capt), on systemic BP, DN progression, BW, GI, and dyslipidemia in OLETF rats. Twenty-four male OLETF rats were divided into the following groups: voluntary exercise alone (OLETF-Ex), Capt administration alone (OLETF-Capt), Capt and exercise (OLETF-Capt & Ex), and sedentary control (OLETF-Sed) groups. Six male Long-Evans Tokushima Otsuka (LETO) rats were used as a normal sedentary control (LETO-Sed). These treatments were conducted from 21 to 30 weeks of age. Approximately 20 mg/kg/day of Capt was administered daily. After the treatment, the OLETF-Ex group experienced decreased BW and improved GI and dyslipidemia; however, it was associated with diastolic BP elevation and DN progression. The OLETF-Capt group experienced decreased BP and serum TG concentration and inhibited DN progression. The OLETF-Capt & Ex group experienced decreased BW and BP, and improved GI and dyslipidemia without the progression of DN. This study demonstrated that a combined treatment of exercise and antihypertensive agents, such as Capt, is recommended as an ideal regimen for hypertensive diabetic patients in the pre-nephropathy stage to avoid DN progression induced by an exercise regimen alone.
... A Number of studies have also indicated that drugs which interfere with the renin-angiotensin system may also decrease levels of advanced glycation end products (AGEs) [51] . ...
... Kidney sections which were stained with H&E observed under a light microscope in a blinded fashion. The glomerulosclerosis (GS) index was determined by a semi-quantitative method as forty glomeruli from each kidney were graded according to the severity of the glomerular damage [17] . ...
... Renin-angiotensin system inhibitors, which induce multifunctional renoprotective effects, have been shown to reduce AGE precursors [94,95] and act as antioxidants against AGEs [96]. Hydralazine, another antihypertensive agent that does not interact with the renin-angiotensin system, has also been reported to protect against nephropathy in diabetic rats and decrease AGE formation both in vitro and in vivo [97]. ...
Dietary contents and their metabolites are closely related to chronic kidney disease (CKD) progression. Advanced glycated end products (AGEs) are a type of uremic toxin produced by glycation. AGE accumulation is not only the result of elevated glucose levels or reduced renal clearance capacity, but it also promotes CKD progression. Indoxyl sulfate, another uremic toxin derived from amino acid metabolism, accumulates as CKD progresses and induces tubulointerstitial fibrosis and glomerular sclerosis. Specific types of amino acids (D-serine) or fatty acids (palmitate) are reported to be closely associated with CKD progression. Promising therapeutic targets associated with nutrition include uremic toxin absorbents and inhibitors of AGEs or the receptor for AGEs (RAGE). Probiotics and prebiotics maintain gut flora balance and also prevent CKD progression by enhancing gut barriers and reducing uremic toxin formation. Nrf2 signaling not only ameliorates oxidative stress but also reduces elevated AGE levels. Bardoxolone methyl, an Nrf2 activator and NF-κB suppressor, has been tested as a therapeutic agent, but the phase 3 clinical trial was terminated owing to the high rate of cardiovascular events. However, a phase 2 trial has been initiated in Japan, and the preliminary analysis reveals promising results without an increase in cardiovascular events.
... In physiological conditions, AGEs are degraded to soluble polypeptides by the mononuclear macrophage system via endocytosis or extracellular protein degradation systems, and are primarily cleared by the kidneys (8). However, in pathological conditions, particularly diabetic complications, AGEs yet to be eliminated may stimulate the secretion of cytokines from macrophage and mesangial cells, thus leading to vascular hyperplasia, mesangial proliferation and glomerular hypertrophy, which are associated with the development of diabetic nephropathy (9). In addition, AGEs may modify numerous additional proteins, leading to a number of diseases. ...
Advanced glycation end products (AGEs) restrain the proliferation of endothelial cells, which is an important determinant of diabetic vasculopathy. Mitochondrial biogenesis serves an essential role in cellular adaptation and repair. The current study aimed to investigate alterations in mitochondrial energy metabolism in human umbilical vein endothelial cells (HUVECs) and the latent mechanism regulated by AGEs. The proliferation of cultured HUVECs stimulated with AGEs was detected using an MTT assay and a real‑time cell analyzer (RTCA). Mitochondrial energy metabolism was measured using a Seahorse metabolic flux analyzer. Mitochondrial membrane potential was detected under fluorescence microscopy following staining with tetraethylrhodamine and MitoTracker Red. Respiratory chain complexes I‑V were detected using western blotting. MTT and RTCA assays demonstrated that AGEs treatment significantly inhibited the viability and proliferation of HUVECs when compared with bovine serum albumin treatment. Results from the Seahorse metabolic flux analyzer indicated that mitochondrial aerobic respiration and glycolysis declined following AGEs treatment. In addition, mitochondrial membrane potential and the expression of mitochondrial respiration chain complexes I/II/III/IV/V notably decreased in the presence of AGEs. In conclusion, the results of the present study indicated that AGEs exhibited an inhibitory effect on the proliferation in HUVECs potentially by mediating the dysfunction of mitochondrial energy metabolism and glycolysis. This may provide a new consideration for therapeutic methods in diabetic vascular complications.
... The same authors reported significantly lower serum AGEs levels after administration of high-AGE diet combined with orlistat in comparison to high-AGE diet only in women with PCOS [104]. Some other compounds such as angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers, pentoxyfylline, desferoxamine, penicillamine, aspirin, vitamin C or E (antioxidants), amadoriases (enzymes that causes degradation of amadori products), phenacylthiazolium bromide (disrupt α-dicarbonyl cross-link), aryl ureido, and aryl carboxaminido phenoxy isobutyric acids derivatives are being investigated as AGE inhibitors [105][106][107][108][109]. ...
PCOS is the most common cause of anovulation in reproductive-aged women with 70% experiencing ovulatory problems. Advanced glycation end products are highly reactive molecules that are formed by non-enzymatic reactions of sugars with proteins, nucleic acids and lipids. AGEs are also present in a variety of diet where substantial increase in AGEs can result due to thermal processing and modifications of food. Elevation in bodily AGEs, produced endogenously or absorbed exogenously from high-AGE diets, is further exaggerated in women with PCOS and is associated with ovulatory dysfunction. Additionally, increased expression of AGEs as pro-inflammatory receptors in the ovarian tissue has been observed in women with PCOS. In this review, we summarize the role of dietary AGEs as mediators of metabolic and reproductive alterations in PCOS. Once a mechanistic understanding of the relationship between AGEs and anovulation is established, there is a promise that such knowledge will contribute to the subsequent development of targeted pharmacological therapies that will treat anovulation and improve ovarian health in women with PCOS.
