Necrostatin-1 Attenuates Cisplatin-Induced Nephrotoxicity Through Suppression of Apoptosis and Oxidative Stress and Retains Klotho Expression.

Cisplatin is an effective chemotherapeutic drug, but the application in clinical is greatly limited by its nephrotoxicity. Necrostatin-1 (Nec-1), an inhibitor of RIP1 kinase, has been reported to inhibit RIP-mediated necroptosis. The aim of this study is to detect the protective effects of Nec-1 on the nephrotoxicity of cisplatin and to investigate its renoprotection mechanism. 8-week-old male C57BL/6 mice were randomly assigned into four groups: Control, Nec-1, Cisplatin, and Cisplatin+Nec-1. Mice were treated with cisplatin with or without Nec-1 pre-treatment. Renal function, histological changes, necroptosis, and apoptotic markers were investigated. NFκB pathway related proteins, proinflammatory cytokines, oxidative stress markers, renal Klotho, and autophagy-related proteins levels were also examined. Renal function and histological data displayed that the treatment with Nec-1 significantly attenuates cisplatin-induced renal damage. The expression of RIPK1/RIPK3/MLKL were significantly enhanced in cisplatin group as compared to the control group ( < 0.05) and was significantly reduced by pre-treatment of Nec-1 ( < 0.05). The level of stress and apoptosis-related protein, including p-JNK, p-c-Jun, p-p38, Bax/Bcl-2 ratio, and caspase-3 showed the similar trend. Pre-treatment with Nec-1 inhibit NFκB signaling, reduced proinflammatory cytokines and oxidative stress, up-regulated renal Klotho, and autophagy-related proteins levels. Our results suggest that Nec-1 could be a potential therapeutic drug against the cisplatin-induced nephrotoxicity through its anti-necroptosis, anti-apoptotic, anti-inflammatory anti-oxidant and retain Klotho expression and activate autophagy effects in the kidney.