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1 INSERM U858, Toulouse, France
2 Universite Sherbrooke, Canada
3 Biochemistry, CHU Bicetre, Paris, France
4 INSERM U858, Toulouse, France
* To whom correspondence should be addressed. E-mail: girolami{at}toulouse.inserm.fr.
Diabetic nephropathy (DN) is associated with increased oxidative stress, overexpression and activation of growth factor receptors, including those for transforming growth factor 
1 (TGF-RII), platelet derived growth factor (PDGF-R) and insulin-like growth factor (IGF1-R) . These pathways are believed to represent pathophysiological determinants of DN. Beyond perfect glycemic control, angiotensin-converting enzyme inhibitors (ACEI) are the most efficient treatment to delay glomerulosclerosis. Since their mechanisms of action remains uncertain, we investigated the effect of ACEI on the glomerular expression of these growth factor pathways in a model of streptozotocin-induced diabetes in rats. The early phase of diabetes was found to be associated with an increase in glomerular expression of IGF1-R, PDGF-R and TGF--RII and activation of IRS1, Erk 1/2 and Smad 2/3. These changes were significantly reduced by ACEI treatment. Furthermore, ACEI stimulated glutathione peroxidase activity, suggesting a protective role against oxidative stress. ACEI decreased angiotensin II production but also increased bradykinin bioavailability by reducing its degradation. Thus, the involvement of the bradykinin pathway was investigated using co-administration of HOE-140, a highly specific non-peptidic B2-kinin receptor antagonist. Almost all the previously described effects of ACEI were abolished by HOE 140, as was the increase in glutathione peroxidase activity. Moreover, the well-established ability of ACEI to reduce albuminuria was also prevented by HOE 140. Taken together, these data demonstrate that, in the early phase of diabetes, ACEI reverse glomerular overexpression and activation of some critical growth factor pathways and increase protection against oxidative stress and that these effects involve B2-kinin receptor activation.
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