Enhanced Nitric Oxide Synthase‐Nitric Oxide (NOS‐NO) signaling underlies sildenafil amelioration of cyclosporine‐induced nephrotoxicity in rats

Abstract

Studies have demonstrated that the potent immunosuppressive effect of cyclosporine A (CsA) is associated with severe nephrotoxicity. However, the mechanism(s) of CsA‐mediated nephrotoxicity are understudied. This study aimed to investigate the possible protective effect of sildenafil on CsA‐induced nephrotoxicity and whether this effect is mediated via enhanced NOS‐NO signaling. Wistar rats were administered sildenafil (5 mg/kg, p.o) for 21 days alone or in combination with CsA 20 mg/kg, s.c. or with the non‐selective NOS inhibitor L‐NAME; 10 mg/kg, i.p. or both. Control groups were treated with either vehicle, CsA or L‐NAME. Renal functions (serum urea and creatinine, creatinine clearance and albumin‐creatinine ratio), indices of antioxidant activities (catalase, reduced glutathione and malondialdehyde), total nitrate/nitrite (NOx) were measured. Apoptotic and inflammatory markers (caspase‐3 and TNF‐alpha) were measured by. CsA administration for 21 days resulted in significant renal oxidative stress, deterioration of renal functions, reduction of NOx levels, marked apoptotic effect and elevation of nephritic TNF‐alpha expression. Concomitant treatment with sildenafil significantly improved CsA‐renal dysfunction, elevated NOx levels and reduced nephritic oxidative stress. Furthermore, sildenafil attenuated CsA‐evoked apoptosis and TNF‐alpha expression. Interestingly, L‐NAME reversed sildenafil protective effects against CsA‐mediated nephrotoxicity. Taken together, the current study highlights the clinically significant sildenafil protective effects against CsA‐induced nephrotoxicity that might be mediated via enhanced NOS‐NO signaling.