Reduction of the Accumulation of Advanced Glycation End Products by ACE Inhibition in Experimental Diabetic Nephropathy

Abstract

The effect of ACE inhibition on the formation of advanced glycation end products (AGEs) and oxidative stress was explored. Streptozocin-induced diabetic animals were randomized to no treatment, the ACE inhibitor ramipril (3 mg/l), or the AGE formation inhibitor aminoguanidine (1 g/l) and followed for 12 weeks. Control groups were followed concurrently. Renal AGE accumulation, as determined by immunohistochemistry and both serum and renal fluorescence, were increased in diabetic animals. This was attenuated by both ramipril and aminoguanidine to a similar degree. Nitrotyrosine, a marker of protein oxidation, also followed a similar pattern. The receptor for AGEs, gene expression of the membrane-bound NADPH oxidase subunit gp91phox, and nuclear transcription factor-kappaB were all increased by diabetes but remained unaffected by either treatment regimen. Two other AGE receptors, AGE R2 and AGE R3, remained unchanged for the duration of the study. The present study has identified a relationship between the renin-angiotensin system and the accumulation of AGEs in experimental diabetic nephropathy that may be linked through oxidative stress

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

“…Although we used similar doses of ramipril in our study, ramipril only slightly reduced renal CML accumulation and decreased albuminuria by 30%. Differences in the disease models (type 1 vs type 2 diabetes), resulting in different body composition and, hence, drug metabolism and pharmacokinetics, as well as differences in methods for AGE measurement, may explain the quantitative differences between our work and that of Forbes and colleagues [16]. Inter- estingly, the nephroprotective effect of ramipril in type 2 diabetic nephropathy seems to be limited to the reduction of CML accumulation; pentosidine and 3-DG-imidazole were not affected.…”

“…A recent study in a type 1 diabetic animal model [16] also revealed that reduction of albuminuria by ACE inhibition was associated with decreased AGE fluorescence. Although specific AGE were not analysed in this study, the protective effect was similar to that of the AGE inhibitor aminoguanidine [16]. Although we used similar doses of ramipril in our study, ramipril only slightly reduced renal CML accumulation and decreased albuminuria by 30%.…”

“…Recently, the ACE inhibitor ramipril was demonstrated to reduce renal and serum AGE in a type 1 diabetic, hypertensive rat model [16]. These data provide evidence for a previously unknown mechanism of action of ramipril, beyond its direct inhibition of the formation of angiotensin II.…”

A developmental nephron deficit in rats is associated with increased susceptibility to a secondary renal injury due to advanced glycation end-products

“…The factors leading to increased AGE accumulation in animals with a reduced number of nephrons remain to be established. In previous studies in diabetes, reduced renal filtration of circulating AGEs and increased AGE formation associated with hyperglycaemia have been linked to renal AGE accumulation in patients with diabetic nephropathy [29,30]. However, mechanisms other than GFR and dysglycaemia appear to contribute to AGE accumulation in the LPD model.…”

Renoprotective effects of vasopeptidase inhibition in an experimental model of diabetic nephropathy

“…Immunohistochemistry for the ACE protein was carried out on 16 µm paraffin sections as previously described [36,37]. Formalin-fixed paraffin sections were dewaxed, hydrated and incubated using a specific primary antibody raised against rat ACE (Chemicon, Tenecula, Calif., USA) at a dilution of 1/400.…”