Anti-Hypertensive Agents Inhibit In Vivo the Formation of Advanced Glycation End Products and Improve Renal Damage in a Type 2 Diabetic Nephropathy Rat Model

Abstract

Abstract. Prevention or retardation of diabetic nephropathy (DN) includes anti-hypertensive treatment with angiotensinconverting 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 hypertensive/NIHcorpulent rats [SHR/NDmc-cp (fat/fat)] as a model of type II DN to unravel the renoprotective effects of anti-hypertensive drugs. Olmesartan (1 or 5 mg/kg per d), an ARB, and hydralazine (5mg/kg per d), an anti-hypertensive drug without effect on the renin-angiotensin system (RAS), were given for 20 wk. BP, renal function, glucose and insulin levels, and proteinuria were monitored. Glomerular lesions and kidney pentosidine content were assessed at the end of the study. Olmesartan (1 and 5 mg) significantly reduced BP and kidney pentosidine content and improved histologic renal damage and proteinuria.The changes were dose-dependent. The effect of hydralazine (5 mg) was similar to that of olmesartan (1 mg) but reached statistical significance only for kidney pentosidine content. The similarity of both drugs' effects on kidney damage and proteinuria suggest that renoprotection does not hinge on manipulation of RAS in these rats. By contrast, the inhibition of renal pentosidine formation assessed both by immunohistochemistry and HPLC suggests a critical role of advanced glycation end product (AGE) formation together with hypertension in the genesis of diabetic nephropathy. This view is supported by the correlation found between renal pentosidine content and proteinuria. The unsuspected AGE-lowering effect of hydralazine was further confirmed in vitro and elucidated; it is due to both reactive carbonyl compounds trapping and modifications of the oxidative metabolism. It is concluded that AGE inhibition should be included in the therapeutic strategy of DN.Diabetic nephropathy (DN) increases dramatically worldwide and is now the first cause of end-stage renal failure requiring renal replacement therapy (reviewed in references 1 and 2). Its prevention or retardation has thus become an important issue in biomedical research.Several large clinical trials have recently demonstrated that control of hypertension by angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II type 1 receptor blocker (ARB) significantly delayed the onset and progression of DN (3-5). This effect is due to the reduction of BP together with as-yet undefined additional mechanisms. Only studies of adequate experimental models will allow an in-depth exploration of DN pathogenic mechanisms and thus the development of newer therapeutic tools.In the present study, we use a strain of a spontaneously hypertensive/NIH-corpulent rat [SHR/NDmc-cp (fat/fat)] as a model of type 2 DN (6) to unravel the mechanisms of the ARB-induced renoprotection against DN. We demonstrate a dose-dependent, renoprotective effect of olmesartan, which is an ARB associated with the inhibition of advanced glycation en...

Renal accumulation and clearance of advanced glycation end-products in type 2 diabetic nephropathy: effect of angiotensin-converting enzyme and vasopeptidase inhibition

“…We found that the active metabolite of AVE7688 (AVE8048) but not that of ramipril (ramiprilat) inhibited the formation of CML and pentosidine in vitro. Recent investigations on antihypertensive drugs revealed that renin-angiotensin system inhibitors, such as ACE inhibitors and angiotensin II type 1 receptor blockers, also inhibited AGE formation in vitro and in vivo [41,42]. Unlike established AGE inhibitors such as aminoguanidine, which trap reactive carbonyl precursors, the ACE inhibitors and angiotensin II type 1 receptor blockers, which do not have carbonyl-reactive functional groups, may inhibit the production of reactive carbonyl precursors by chelating transition metals and inhibiting various oxidative steps at both the pre-and the post-Amadori stage [41,42].…”

“…Recent investigations on antihypertensive drugs revealed that renin-angiotensin system inhibitors, such as ACE inhibitors and angiotensin II type 1 receptor blockers, also inhibited AGE formation in vitro and in vivo [41,42]. Unlike established AGE inhibitors such as aminoguanidine, which trap reactive carbonyl precursors, the ACE inhibitors and angiotensin II type 1 receptor blockers, which do not have carbonyl-reactive functional groups, may inhibit the production of reactive carbonyl precursors by chelating transition metals and inhibiting various oxidative steps at both the pre-and the post-Amadori stage [41,42]. Therefore, we investigated the chelating potential of the active metabolites of AVE7688 (AVE8048) and ramipril (ramiprilat) and compared them with the AGE inhibitors pyridoxamine and tenilsetam [21], using an assay based on inhibition of copper-catalysed oxidation of ascorbic acid.…”

Effect of antioxidants and ACE inhibition on chemical modification of proteins and progression of nephropathy in the streptozotocin diabetic rat

“…In support of this hypothesis, aldose reductase inhibitors, which protect against the development of nephropathy in the diabetic rat, also inhibit AGE formation [11]. Similarly, ACE inhibitors and angiotensin receptor antagonists inhibit the formation of AGE in the kidney of diabetic rats [12,13].…”

“…The AGE hypothesis has been supported by studies demonstrating that treatment with AGE inhibitors, such as aminoguanidine [1,8], OPB-9195 (2-isopropylidenehydrazono-4-oxo-thiazolidin-5-yl-acetanilide) [9] and pyridoxamine [10], has a profound inhibitory effect on the development of a range of complications, including nephropathy, in diabetic animals. However, despite the clear association between AGE and diabetic complications and the protective effects of AGE inhibitors, the results of other studies suggest that AGE are not directly involved in the pathogenesis of diabetic complications: thus aldose reductase inhibitors [11], ACE inhibitors and angiotensin receptor antagonists [12,13,14], protein kinase C inhibitors [15,16], cerivastatin (a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor) [17] and benfotiamine (or thiamine) [18] have all been shown to have beneficial effects in animal models and/or clinical studies.…”

“…Vitamin E [19,20,21], lipoic acid [22,23,24,25,26] and ACE inhibitors [12,13] have been shown to protect against diabetic complications in animal models, but their effects on AGE formation have not been evaluated by chemical methods. In the present work, experiments with vitamin E were designed primarily to address the role of lipid peroxidation in the formation of AGE/ALE, while recognising that it is also an inhibitor of protein kinase C [15].…”