Necrostatin-1 attenuates cisplatin-induced nephrotoxicity through suppression of apoptosis and oxidative stress and retains Klotho expression

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Abstract

Aim: 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. Methods: 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. Results: 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 (p < 0.05) and was significantly reduced by pre-treatment of Nec-1 (p < 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. Conclusion: 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.

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Ning, Y., Shi, Y., Chen, J., Song, N., Cai, J., Fang, Y., … Ding, X. (2018). Necrostatin-1 attenuates cisplatin-induced nephrotoxicity through suppression of apoptosis and oxidative stress and retains Klotho expression. Frontiers in Pharmacology, 9(APR). https://doi.org/10.3389/fphar.2018.00384

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