Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Advanced glycation endproducts (AGEs) have been postulated to play a role in the development of both nephropathy and large vessel disease in diabetes. However, it is still not clear which AGE subtypes play a pathogenetic role and which of several AGE receptors mediate AGE effects on cells. This review summarises the renoprotective effect of inhibitors of AGE formation, including aminoguanidine, and of cross-link breakers, including ALT-711, on experimental diabetic nephropathy and on mesenteric vascular hypertrophy. It also demonstrates similar effects of aminoguanidine and ramipril (an angiotensin converting enzyme inhibitor) on fluorescent and immunoassayable AGE levels, renal protein kinase C activity, nitrotyrosine expression, lysosomal function, and protein handling in experimental diabetes. These findings indicate that inhibition of the renin angiotensin system blocks both upstream and downstream pathways leading to tissue injury. We postulate that the chemical pathways leading to advanced glycation endproduct formation and the renin angiotensin systems may interact through the generation of free radicals, induced both by glucose and angiotensin II. There is also evidence to suggest that AGE-dependent pathways may play a role in the development of tubulointerstitial fibrosis in the diabetic kidney. This effect is mediated through RAGE and is TGF-beta and CTGF-dependent.
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PMID:Evolving concepts in advanced glycation, diabetic nephropathy, and diabetic vascular disease. 1456 9

There is a growing body of evidence that the advanced glycation end product (AGE)-their receptor (RAGE) system plays a central role in the pathogenesis of diabetic vascular complication. The renin-angiotensin system (RAS) contributes to the development and progression of diabetic angiopathy as well. However, the cross-talk between the AGE-RAGE system and the RAS is not fully understood. In this study, we examined the role of angiotensin II (Ang II) type 1 receptor system for RAGE expression in cultured endothelial cells (ECs) and in patients with essential hypertension. Ang II up-regulated RAGE mRNA levels of microvascular ECs and subsequently increased the soluble form of RAGE (sRAGE) expression in the medium of ECs, both of which were completely blocked by telmisartan, a commercially available Ang II type 1 receptor antagonist. Furthermore, telmisartan was found to decrease serum levels of sRAGE in patients with essential hypertension. These results demonstrate that sRAGE is released from the cell surface of Ang-II-exposed ECs. Our present study indicates that a cross-talk exists between the AGE-RAGE system and the RAS and suggests that serum levels of sRAGE may reflect endothelial RAGE expression.
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PMID:Telmisartan inhibits expression of a receptor for advanced glycation end products (RAGE) in angiotensin-II-exposed endothelial cells and decreases serum levels of soluble RAGE in patients with essential hypertension. 1627 39

Diabetes mellitus affects about 8% of the adult population. The estimated number of patients with diabetes, presently about 170 million people, is expected to increase by 50-70% within the next 25 years. Diabetes is an important component of the complex of 'common' cardiovascular risk factors, and is responsible for acceleration and worsening of atherothrombosis. Major cardiovascular events cause about 80% of the total mortality in diabetic patients. Diabetes also induces peculiar microangiopathic changes leading to diabetic nephropathy conducive to end-stage renal failure, and to diabetic retinopathy that may progress to vision loss and blindness. In terms of major cardiovascular events, coronary heart disease and ischaemic stroke are the main causes of morbidity and mortality in diabetic patients. Peripheral arterial disease frequently occurs, and is more likely to be conducive to critical limb ischaemia and amputation than in the absence of diabetes. Although there are a number of differences in the pathogenesis and clinical features of diabetic macroangiopathy and microangiopathy, these two entities often coexist and induce mutually worsening effects. Endothelial injury, dysfunction and damage are common starting points for both conditions. Causes of endothelial injury can be distinguished into those 'common' to nondiabetic atherothrombosis, such as hypertension, dyslipidaemia, smoking, hypercoagulability and platelet activation; and those more specific and in some cases 'unique' to diabetes and directly related to the metabolic derangement of the disease, such as (i) desulfation of glycosaminoglycans (GAGs) of the vascular matrix; (ii) formation of advanced glycation end-products (AGE) and their endothelial receptors (RAGE); (iii) oxidative and reductive stress; (iv) decline in nitric oxide production; (v) activation of the renin-angiotensin aldosterone system (RAAS); and (vi) endothelial inflammation caused by glucose, insulin, insulin precursors and AGE/RAGE. Prevention of major cardiovascular events with the antithrombotic agent aspirin (acetylsalicylic acid) is widely recommended, but reportedly underutilised in patients with diabetes. However, some data suggest that aspirin may be less effective than expected in preventing cardiovascular events and especially mortality in patients with diabetes, as well as in slowing progression of retinopathy. In contrast, a recent study found picotamide, a direct thromboxane inhibitor, to be superior to aspirin in diabetic patients. Clopidogrel was either equivalent or less active in diabetic versus nondiabetic patients, depending upon different clinical settings.Recent studies have shown that some GAG compounds are able to reduce micro- and macroalbuminuria in diabetic nephropathy, and hard exudates in diabetic retinopathy, but it is as yet unknown whether these agents also influence the natural history of microvascular complications of diabetes. Lifestyle changes and physical exercise are also essential in preventing cardiovascular events in diabetic patients. Available data on the control of the metabolic state and the main risk factors show that careful adjustment of blood sugar and glycated haemoglobin is more effective in counteracting microvascular damage than in preventing major cardiovascular events. The latter objective requires a more comprehensive approach to the whole constellation of risk factors both specific for diabetes and common to atherothrombosis. This approach includes lifestyle modifications, such as dietary changes and smoking cessation and the use of HMG-CoA reductase inhibitors (statins), which are able to correct the lipid status and to prevent major cardiovascular events independently of the baseline lipidaemic or cardiovascular status. Tight control of hypertension is essential to reduce not only major cardiovascular events but also microvascular complications. Among antihypertensive measures, blockade of the RAAS by means of ACE inhibitors or angiotensin II receptor antagonists recently emerged as a potentially polyvalent approach, not only for treating hypertension and reducing cardiovascular events, but also to prevent or reduce albuminuria, counteract diabetic nephropathy and lower the occurrence of new type 2 diabetes in individuals at risk.
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PMID:Approaches to prevention of cardiovascular complications and events in diabetes mellitus. 1748 45

We have previously shown that advanced glycation end products (AGEs)-their receptor (RAGE) interaction elicits angiogenesis through autocrine production of vascular endothelial growth factor (VEGF), thus suggesting the active involvement of the AGEs-RAGE system in proliferative diabetic retinopathy (PDR). Since the crosstalk between the AGEs-RAGE and the renin-angiotensin system has also been proposed in the pathogenesis of PDR, we investigated here whether olmesartan, an angiotensin II type 1 receptor blocker, inhibited the AGEs-elicited angiogenesis in vitro by suppressing the NF-kappaB-mediated RAGE expression. Olmesartan significantly inhibited the AGEs-induced NF-kappaB promoter activity and RAGE gene expression in cultured microvascular endothelial cells (ECs). Further, olmesartan was found to block the AGEs-induced up-regulation of VEGF mRNA levels and consequent increase in DNA synthesis in ECs. These results demonstrated for the first time that olmesartan inhibited the AGEs signaling to angiogenesis by suppressing RAGE expression in ECs. Our present study suggests that blockade of the renin-angiotensin system by olmesartan may play a protective role against PDR by attenuating the deleterious effects of AGEs via down-regulation of RAGE.
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PMID:Olmesartan blocks advanced glycation end products (AGEs)-induced angiogenesis in vitro by suppressing receptor for AGEs (RAGE) expression. 1756 Jun 13

Diabetic retinopathy is a common and potentially devastating microvascular complication in diabetes and is a leading cause of acquired blindness among the people of occupational age. However, current therapeutic options for the treatment of sight-threatening proliferative diabetic retinopathy such as photocoagulation and vitrectomy are limited by considerable side effects and far from satisfactory. Therefore, to develop novel therapeutic strategies that specifically target diabetic retinopathy is actually desired for most of the patients with diabetes. Chronic hyperglycemia is a major initiator of diabetic retinopathy. However, recent clinical study has substantiated the concept of 'hyperglycemic memory' in the pathogenesis of diabetic retinopathy. Indeed, the Diabetes Control and Complications Trial-Epidemiology of Diabetes Interventions and Complications (DCCT-EDIC) Research, has revealed that the reduction in the risk of progressive retinopathy resulting from intensive therapy in patients with type 1 diabetes persisted for at least several years after the DCCT trial, despite increasing hyperglycemia. These findings suggest a long-term beneficial influence of early metabolic control on clinical outcomes in type 1 diabetic patients. Among various biochemical pathways implicated in the pathogenesis of diabetic retinopathy, the process of formation and accumulation of advanced glycation end products (AGEs) and their mode of action are most compatible with the theory 'hyperglycemic memory'. Further, there is a growing body of evidence that AGEs-RAGE (receptor for AGEs) interaction-mediated oxidative stress generation plays an important role in diabetic retinopathy. This article summarizes the role of AGEs and oxidative stress in the development and progression of diabetic retinopathy and the therapeutic interventions that could prevent this devastating disorder. We also discuss here the pathological crosstalk between the AGEs-RAGE and the renin-angiotensin system in diabetic retinopathy and a potential clinical utility of telmisartan, an angiotensin II type 1 receptor blocker with peroxisome proliferator-activated receptor-gamma-modulating activity.
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PMID:Role of advanced glycation end products (AGEs) and oxidative stress in diabetic retinopathy. 1847 46

Advanced glycation end-products (AGEs) are generated in the diabetic milieu, as a result of chronic hyperglycemia and enhanced oxidative stress. These AGEs, via direct and receptor dependent pathways promote the development and progression of cardiovascular disease. AGEs accumulate at many sites of the body including the heart and large blood vessels in diabetes. These modified proteins interact with receptors such as RAGE to induce oxidative stress, increase inflammation by promoting NFkappaB activation and enhance extracellular matrix accumulation. These biological effects translate to accelerated plaque formation in diabetes as well as increased cardiac fibrosis with consequent effects on cardiac function. Strategies to reduce the ligation of AGEs to their receptors such as agents which reduce AGE accumulation, soluble RAGE which acts as a competitive antagonist to the binding of AGEs to RAGE and genetic deletions of RAGE appear to attenuate diabetes associated atherosclerosis. Benefits on cardiac dysfunction with these inhibitors of the AGE/RAGE axis are not as well characterised. In conclusion, therapeutic strategies targeting AGEs appear to have significant clinical potential, often in combination with currently used agents such as inhibitors of the renin-angiotensin system, to reduce the major burden of diabetes, its associated cardiovascular complications.
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PMID:The role of AGEs in cardiovascular disease. 1847 49

Steno-2 Study has previously shown that intensified multifactorial intervention reduces the risk of nonfatal cardiovascular disease in patients with type 2 diabetes. Further, in the recent follow-up study, intensive therapy was found to have sustained beneficial effects on cardiovascular events and death in this population. A similar outcome was reported in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT-EDIC) Research, which revealed that original intensive therapy reduced the risk of cardiovascular events to about 50% of that of conventional treatment in type 1 diabetic patients 11 years after the end of the trial, although glycosylated hemoglobin values in the two groups had almost converged during the follow-up periods. These two clinical studies strongly suggest that so-called 'metabolic memory' causes chronic vascular damage in diabetic patients, that are not easily reversed, even by subsequent, relatively good control of metabolic risk factors. Potential mechanisms for propagating this 'metabolic memory' are the non-enzymatic glycation of proteins. Indeed, the formation and accumulation of advanced glycation end products (AGEs) have been known to progress at an accelerated rate under diabetes, and there is accumulating evidence that AGEs-their receptor RAGE interaction elicits oxidative stress generation and subsequently evokes vascular inflammation, thus being involved in the pathogenesis of accelerated atherosclerosis in diabetes. Since renin-angiotensin system inhibitors or a lipid-lowering agent, atorvastatin, not only inhibit the AGE-signaling to inflammation, but also reduce serum levels of AGEs in type 2 diabetic patients, it is conceivable that the carry-over beneficial effects of multifactorial intervention on cardiovascular events and death in the follow-up Steno-2 Study could be ascribed, at least in part, to its inhibitory effects on AGE formation and/or the downstream-signaling pathways. Therefore, it is interesting to clarify whether circulating or skin AGE levels at the closure of Steno-2 Study could predict cardiovascular events at the end of the trial. This clinical investigation may provide us more information about whether blockade of the AGE-RAGE system is one of the mechanisms for sustained beneficial effects of multifactorial intervention on mortality in type 2 diabetes.
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PMID:Blockade of the advanced glycation end products (AGEs) and their receptor (RAGE) system is a possible mechanism for sustained beneficial effects of multifactorial intervention on mortality in type 2 diabetes. 1871 Jul 93

1. Advanced glycation end-products (AGE) and their receptors (RAGE) have been implicated in renal damage in diabetes. The aim of the present study was to investigate the effects of benazepril, an angiotensin-converting enzyme inhibitor (ACEI), on the formation of AGE, the expression RAGE and other associated components in the oxidative stress pathway in spontaneously hypertensive rats (SHR). 2. Groups of SHR were treated with or without 10 mg/kg per day benazepril for 12 weeks. Systolic blood pressure (SBP) and angiotensin (Ang) II levels were evaluated in SHR and control Wistar-Kyoto (WKY) rats. Renal function was investigated by determining levels of proteinuria and glomerulosclerosis. Furthermore, reactive oxygen species (ROS) in the rat renal cortex were analysed using an H(2)O(2)-based hydroxyl radical-detection assay and the renal content of AGE, RAGE, NADPH oxidase p47phox, nuclear factor (NF)-kappaB p65, phosphorylated (p-) NF-kappaB p65, vascular cell adhesion molecule (VCAM)-1 and transforming growth factor (TGF)-beta1 was determined by immunohistochemistry, quantitative real-time polymerase chain reaction and western blot analysis. 3. Treatment with benazepril inhibited the formation of AngII, reduced SBP and alleviated renal lesions in SHR compared with both untreated SHR and control WKY rats. Benazepril treatment significantly suppressed the accumulation of AGE and expression of RAGE in the kidney of SHR. In addition, benazepril treatment reduced the upregulation of NADPH oxidase p47phox, ROS generation and NF-kappaB p65, p-NF-kappaB p65, VCAM-1 and TGF-beta1 expression in the kidney of SHR compared with both untreated SHR and control WKY rats. 4. The results of the present study provide new insights into the regulation by the renin-angiotensin system of AGE-RAGE, oxidative stress and nephropathy, increasing our understanding of the role of the RAS in nephropathy.
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PMID:Benazepril, an angiotensin-converting enzyme inhibitor, alleviates renal injury in spontaneously hypertensive rats by inhibiting advanced glycation end-product-mediated pathways. 1901 97

Approaching epidemic levels, diabetic kidney disease (DKD) is now the leading cause of end-stage renal disease (ESRD). Microalbuminuria is an early clinical marker of DKD that results from damage to the glomerular filtration barrier at the level of the highly differentiated glomerular podocyte cells. Injury to these epithelial cells, podocytopathies, includes cellular hypertrophy, foot process effacement, detachment from the glomerular basement membrane, and apoptosis. Here we review the role of a number of recently identified factors that contribute to podocytopathies in DKD. These factors include members of the renin-angiotensin system (RAS), including angiotensin-converting enzyme (ACE) types 1 and 2, prorenin and its receptor, reactive oxygen species (ROS), prostanoids, peroxisome proliferator-activated receptors (PPAR), advanced glycation end-products (AGEs) and their receptors (RAGE), adiponectin, and microRNAs. As the number of therapeutic options that slow, but do not halt, the progression of DKD to ESRD remains limited, a more comprehensive understanding of the signaling events that contribute to this increasingly prevalent disease may identify novel avenues for treatment and prevention.
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PMID:The podocyte in diabetic kidney disease. 1983 99

Diabetic nephropathy is a leading cause of end-stage renal disease. Statins may exert renoprotective effects independently of lipid-lowering properties. We investigated the pleiotropic effects of rosuvastatin on renal structure and function in streptozotocin diabetic apolipoprotein-E knockout (Apo-E(-/-)) mice, a model of progressive nephropathy in which dyslipidemia is resistant to statin treatment. These effects were compared with those observed with conventional renin-angiotensin system blockade (candesartan) or combined treatment. Nondiabetic and diabetic Apo-E(-/-) mice were randomized to no treatment or treatment with candesartan (2.5 mg/kg), rosuvastatin (5 mg/kg), or their combination per gavage for 20 wk. Urine and blood samples were collected for assessment of albuminuria, creatinine clearance, plasma lipids, glucose, and glycated hemoglobin. Renal sclerosis was analyzed on paraffin-embedded kidney sections stained with periodic acid-Schiff. Renal expression of collagen IV, fibronectin and advanced glycation end products (AGEs), receptor for advanced glycation and products (RAGE), NADPH oxidase 4 (NOX4), and nitrotyrosine was assessed by real-time PCR and/or immunohistochemistry. Diabetes-induced albuminuria was not affected by rosuvastatin and combination treatment but was prevented by candesartan. Diabetes resulted in increased creatinine clearance, which was not modified by the treatments. Rosuvastatin and/or candesartan prevented diabetes-associated renal extracellular matrix accumulation. Rosuvastatin reduced accumulation of AGEs and expression of RAGE, NOX4, and nitrotyrosine. In conclusion, in the diabetic Apo-E(-/-) mouse, rosuvastatin confers renal benefits that are independent of lipid lowering and equivalent or greater to those observed with candesartan. The combination treatment is not superior to monotherapies.
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PMID:The pleiotropic actions of rosuvastatin confer renal benefits in the diabetic Apo-E knockout mouse. 2055 45


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