O37	Role of the ACE gene in renal and vascular complications of diabetes mellitus, experimental study in the mouse.
N.Bouby, N.Goncalves, C.Chollet, L.Cheval, M.Marre, F.Alhenc-Gelas
INSERM Units 652 and 695, Paris, FR.

Diabetic nephropathy (DN) is associated, since its incipient stage, with an increased incidence of myocardial infarction and major cardiovascular events, and is a potent cardiovascular risk factor. Several clinical studies have shown association between the onset and the progression of DN in type I diabetes, or the incidence of myocardial infarction in type I and type II diabetes, and the genetic polymorphism of angiotensin I-converting enzyme (ACE) levels. Causality between the constitutive level of ACE gene expression and renal involvement in diabetes has been established in mice having three copies of ACE gene and a modest (62%) increase in ACE plasma level. These mice displayed an accelerated nephropathy compared to their diabetic wild type littermates. The present work aimed at elucidating, using this mouse monogenic model, the molecular mechanisms of the early phase of DN and to identify genes related to ACE-dependent disease susceptibility. Transcriptional profiles of glomeruli from control or diabetic mice with 2 or 3 copies of ACE genes have been studied by serial analysis of gene expression two weeks after streptozotocin-induced diabetes. Two series of cDNA banks were constructed from different animals and experiments to test reproducibility. Comparison of 50,000 tags per library identified 231 genes that are regulated by diabetes and 151 regulated by ACE (p<0.01). Some of the most abundant glomerular transcripts are similarly altered by diabetes and by ACE. Preliminary analysis suggests that suppression of genes related to podocyte function (podocin and podocalyxin), or endothelial function (tissue kallikrein) is an early event in DN. A large increase in Thymosin Beta4 , the putative precursor of N-Ac-SDKP, an ACE substrate was also observed. To further assess the rôle of kallikrein in diabetic complications, mice genetically deficient in kallikrein were studied. When rendered diabetics by streptozotocin and followed for two months after diabetes induction these mice displayed an aggravated disease and a significantly exaggerated mortality compared to diabetic wild type littermates. In conclusion ACE plays a deleterious and kallikrein a protective role in diabetes probably through their effects on kinin levels. The ACE mediated diabetic nephropathy involves early alterations in glomerular genes transcription.

Copyright © 2005 S. Karger AG, Basel. Any further use of this abstract requires written permission from the publisher.