0339: Does mineralocorticoid receptor antoganism could alleviate cyclosporin-induced nephrotoxicity in renal transplant recipients?

Abstract

Cyclosporine-induced Nephrotoxicity (CIN) is a major adverse event but its pathophysiology remains unclear. Mineralocorticoid Receptor (MR) pharmacological antagonism prevents CIN in rats by modulating the expression of vasoactive factors. Our team has shown that MR is expressed in endothelial and vascular smooth muscle cells (VSMC). Therefore, genetic MR manipulations in endothelium or VSMC modify vascular function. Our working hypothesis is that vascular MR activation plays a key role in CIN. Female mice with low-salt diet were used: 1) Pharmacological approach: Control (Vehicle), Cyclosporine-A (CsA, 100 mg/kg/d) and CsA + Can (CsA + Canrenoate 30 mg/kg/d, MR antagonist); 2) Genetic approach: MR KO in VSMC (MRKO-VSMC) or in Endothelial Cells (MRKO-EC) treated or not with CsA. Body weight loss is greater in Cyclosporine-treated groups (p<0.05). Renal function is impaired (p<0.05) and CsA induces renal histological damages that are prevented by MR antagonism or by MR KO in VSMC but not in endothelial cells. Canrenoate and MR KO in VSMC also prevent Cyclosporine-induced renal expression (mRNA) of NGAL (Neutrophil Gelatinase Associated Lipocalin), a kidney damage marker. CsA induced NGAL expression in proximal tubules (immunohistochemistry); this effect is prevented by MR antagonism and MR KO in VSMC but not in endothelial cells. We show that MR antagonism has beneficial effect on Cyclosporine-induced renal damages that, at least partially, involve VSMC MR. The underlying cellular mechanisms are currently under investigation. A clinical trial testing the safety of MR antagonism (Eplerenone) in renal transplant recipients treated with Cyclosporine is currently ongoing.