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

Introduction 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. Methods 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. Results Body weight loss is greater in Cyclosporine-treated groups (p Conclusions 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.