Vasopeptidase inhibition prevents nephropathy in Zucker diabetic fatty rats

被引:56
作者
Schäfer, S
Linz, W
Bube, A
Gerl, M
Huber, J
Kürzel, GU
Bleich, M
Schmidts, HL
Busch, AE
Rütten, H
机构
[1] Aventis Pharma Deutschland GMBH, Dis Grp Cardiovasc Dis, D-65926 Frankfurt, Germany
[2] Aventis Pharma Deutschland GMBH, DSE Pathol, D-65926 Frankfurt, Germany
[3] Aventis Pharma Deutschland GMBH, Grp Biomarkers, D-65926 Frankfurt, Germany
[4] Aventis Pharma Deutschland GMBH, Drug Metab & Pharmacokinet, D-65926 Frankfurt, Germany
关键词
Zucker diabetic fatty rat; diabetic nephropathy; angiotensin-converting enzyme inhibitor; vasopeptidase inhibitor;
D O I
10.1016/S0008-6363(03)00544-3
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background: Blocking the renin-angiotensin system is an established therapeutic principle in diabetic nephropathy. We investigated whether inhibition of both neutral endopeptidase and ACE (vasopeptidase inhibition) can prevent functional and morphological features of nephropathy in the Zucker diabetic fatty (ZDF) rat, an animal model of type II diabetes. Methods: Homozygous (fa/fa) ZDF rats (each n = 15) aged 10 weeks were treated with placebo, ramipril (1 mg/kg/day in drinking water), or the vasopeptidase inhibitor AVE7688 (45 mg/ kg/day in chow). Metabolic parameters and renal function (metabolic cages) were assessed at baseline (age 10 weeks), and at age 17, 27, and 37 weeks. Twenty heterozygous animals (fa/-) served as lean, nondiabetic controls. At age 37 weeks, the animals were sacrificed and the kidneys analyzed histopathologically. Results: Overt diabetes mellitus (blood glucose > 20 mmol/l) was established at age 17 weeks in all homozygous ZDF rats. In the placebo group, urinary protein excretion increased progressively from 8 +/- 1 (baseline) to 342 +/- 56 mg/kg/day (week 37) whereas diabetes and proteinuria were absent in the lean control group. Ramipril tended to reduce albuminuria and morphological damage (p = ns) but AVE7688 virtually prevented albuminuria (33 +/- 12 mg/kg/day, p < 0.05 vs. ZDF placebo) and drastically reduced the incidence and severity of glomerulosclerosis and tubulointerstitial damage. Conclusions: In ZDF rats, development of diabetes mellitus is accompanied by functional and morphological kidney damage that resembles human diabetic nephropathy. Diabetic nephropathy can be prevented by chronic vasopeptidase inhibition. (C) 2003 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
引用
收藏
页码:447 / 454
页数:8
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