Protevtive effects of necrostatin-1 on cisplatin nephrotoxicity in isolated perfused rat ki̇dney

Cisplatin is one of the most effective agent in cancer chemotherapy and being used to treat various solid tumors. Nephrotoxicity is one of the major, dose-limiting side effects of cisplatin. It has been known that different mechanisms contribute to nephrotoxicity of cisplatin and oxidative stress is one of the foremost mechanisms of all. In recent years, studies performed with antioxidant agents, has shown that nephrotoxic effects of cisplatin may be prevented by antioxidants via different mechanims. This study was performed to investigate the effect of Necrostatin-1-which supresses necroptosis by inhibiting RIP-1kinase activity on cisplatin nephrotoxicity. Changes of, renal perfusion pressures and morphologic structures of rat kidneys, compared with the group treated with cisplatin, which is known by its nephrotoxic effects. For this purpose, male Sprague-Dawley rats were divided into 4 groups (n=8): 1- Control 2- Cisplatin (a single dose of cisplatin; 5 mg/kg , i.p.) 3- Single dose of cisplatin (5 mg/kg, i.p.) + Nec-1 (1,65 mg/kg/day, i.p for 5 days), 4- Necrostatin-1 (1,65mg/kg/day, i.p. for 5 days). After five days , all pretreated rats were operated under anesthesia and kidneys were isolated. One of the isolated kidneys was set on the langendorff system via renal arthery and perfused with Krebs-Henseleit solution which was heated (37 Co) and aerated with carbogen (5%CO2 in O2), by a perfusion pump.Perfusion pressures, serum urea and creatinine levels, tissue MDA levels and histopathological changes were compared in all groups. In cisplatin group (a single dose 5 mg/kg, i.p) comparing with control group, perfusion pressures, serum urea and creatinine levels and tissue MDA levels were increased significantly (p<0.01). That increased parameters in cisplatin group were all significantly decreased in Cisplatin + Necrostatin-1 treated group (p<0.05, p<0.01). Histopathologically, in cisplatin treated group glomeruler damage and dilatation of both tubulus was observed. On contrary in cisplatin + Necrostatin1 group less glomerular and tubular damage was observed in glomerules and both tubules. With our findings, it is concluded that necrostatin-1 has protective effects on cisplatin induced nephrotoxicity.