QUINAPRIL DECREASES RENAL ENDOTHELIN-1 EXPRESSION AND SYNTHESIS IN A NORMOTENSIVE MODEL OF IMMUNE-COMPLEX NEPHRITIS

Angiotensin-converting enzyme (ACE) inhibitors diminish proteinuria an d the progression to renal failure in several experimental models of r enal injury. Endothelin-1 (ET-1) possesses potent biological actions o n renal vessels and has been considered as a potential mediator of ren al damage. Because angiotensin II (Ang II) induces ET-1 synthesis in e ndothelial and mesangial cells, we hypothesized that some of the benef icial effects of the ACE inhibitors could result from the blockade of ET-1 synthesis. In a normotensive model of immune-complex nephritis, i n which there exists an increase in renal ACE activity, the effect of the ACE inhibitor quinapril on preproET-1 and ETA receptor mRNA expres sion, as well as on ET-1 protein levels, was examined in this study. I n relation to controls, nephritic rats showed an increase in preproET- 1 and ETA receptor gene expression in renal cortex and medulla, coinci ding with the maximal renal ACE activity. PreproET-1 mRNA (in situ hyb ridization) and ET-1 protein (immunohistochemistry) were localized in glomerular capillary walls, mesangial and glomerular epithelial cells, as well as in the blush border of some proximal tubules, and in small vessels. In nephritic rats, there was an increase in preproET-1 mRNA levels and ET-1 protein in all of these areas, without modification of their distribution. The administration of the ACE inhibitor quinapril decreased proteinuria and morphological lesions, preproET-1 gene tran scription, and ET-1 protein levels, as well as the ETA receptor mRNA. The results from this study show that in a normotensive model of immun e-complex nephritis, there was an overexpression of ET-1 in several st ructures of the kidney that was downregulated by quinapril administrat ion. The beneficial effect of ACE inhibitors could be a result of the modulation of local production of Ang II and ET-1.