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

• Main Authors: Yichun Ning (Author), Yiqin Shi (Author), Jing Chen (Author), Nana Song (Author), Jieru Cai (Author), Yi Fang (Author), Xiaofang Yu (Author), Jun Ji (Author), Xiaoqiang Ding (Author)
• Format: Book
• Published: Frontiers Media S.A., 2018-04-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 1663-9812; 10.3389/fphar.2018.00384
• Keywords: cisplatin; Necrostatin-1; necroptosis; apoptosis; inflammation; oxidative stress; Therapeutics. Pharmacology; RM1-950
• Source: Frontiers in Pharmacology, Vol 9 (2018)

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.