Therapeutic benefit of spironolactone in experimental chronic cyclosporine A nephrotoxicity

Abstract

Cyclosporine A (CsA) is an immunosuppressive drug used to prevent tissue allograft rejection. However, its long-term utilization is limited due to chronic nephrotoxicity for which no prevention is available. This study evaluated the effect of spironolactone on renal functional and structural alterations induced by CsA, and assessed whether the protective effect was associated with a reduction of transforming growth factor-beta (TGF-beta) and the change of extracellular matrix protein mRNA level. Male Wistar rats fed with low sodium diet were divided in four treatment groups: vehicle, CsA (30 mg/kg), spironolactone (20 mg/kg), or CsA+spironolactone. After 21 days, creatinine clearance (CCr), blood CsA, arteriolopathy in renal tissue, and TGF-beta, collagen I, collagen IV, fibronectin, and epidermal growth factor (EGF) mRNA levels in renal cortex were determined. CsA reduced the CCr and up-regulated TGF-beta, collagen I and fibronectin mRNA expression with a significant development of arteriolopathy, and reduced EGF mRNA levels. In contrast, spironolactone administration prevented the fall in renal function and TGF-beta, collagen I, and fibronectin up-regulation, together with a reduction of arteriolopathy and tubulointerstitial fibrosis. Our data show that aldosterone plays an important role as a mediator of renal injury induced by CsA. Thus, mineralocorticoid receptor blockade may be a potential strategy to prevent CsA nephrotoxicity.