Raloxifene Protects Cisplatin-Induced Renal Injury in Mice via Inhibiting Oxidative Stress

Jian-Hong An,1 Chun-Yan Li,1 Chun-Ya Chen,1 Jian-Bin Wu,2 Hong Shen1,3 1School of Medicine, South China University of Technology, Guangzhou Higher Education Mega Center, Guangzhou, 510006, People’s Republic of China; 2Department of Oncology, First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510405, People’s Republic of China; 3Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, People’s Republic of ChinaCorrespondence: Hong Shen Tel +86 20-61648227Fax +86 20-61648312Email shenhong2010168@163.comPurpose: Cisplatin is one of the most widely used antineoplastic drugs but has limited therapeutic effects due to nephrotoxicity. The aim of this study was to determine the possible renoprotective effect of the antioxidant raloxifene on cisplatin-induced nephrotoxicity in mice.Materials and Methods: Cisplatin-induced acute renal injury was established in female C57 mice that were treated with saline (normal control) or raloxifene over a 7-day period. The body weight of the mice was recorded. Histopathological examinations of the kidney tissues were performed using H&E, PAS staining and TEM. The histomorphology of liver and other organs was observed by H&E staining. The serum levels of creatinine, blood urea nitrogen (BUN), alanine transaminase (ALT) and glutamic oxalacetic transaminase (AST) were analyzed by specific kits. Superoxide dismutase (SOD) and glutathione (GSH) activity, and the content of malondialdehyde (MDA) in the kidney, liver homogenates and HK-2 cells were measured by WST-8 and thiobarbituric acid colorimetric methods. Moreover, the mitochondrial structures of HK-2 cells were performed using TEM. The viability and proliferation of HK-2 cells were examined by CCK-8 and EdU incorporation assays. The mitochondrial membrane potential was measured by JC-1 fluorescence.Results: Raloxifene significantly reduced the levels of serum creatinine, urea, ALT and AST in the cisplatin-treated mice, and alleviated cisplatin-induced renal and hepatic tissue injury. Furthermore, raloxifene also increased the activity of GSH and SOD in the renal tissues and HK-2 cells, and reduced MDA levels, thereby limiting oxidative stress in the kidney.Conclusion: Raloxifene protected against cisplatin-induced nephrotoxicity by activating the antioxidant system, along with alleviating liver damage. It should be considered as a potential adjuvant in cisplatin-based chemotherapeutic protocols.Keywords: raloxifene, cisplatin, nephrotoxicity, hepatotoxicity, oxidative stres