Mitochondrial-targeted antioxidants represent a promising approach for prevention of cisplatin-induced nephropathy

作者：Mukhopadhyay Partha; Horvath Bela; Zsengeller Zsuzsanna; Zielonka Jacek; Tanchian Galin; Holovac Eileen; Kechrid Malek; Patel Vivek; Stillman Isaac E; Parikh Samir M; Joseph Joy; Kalyanaraman Balaraman; Pacher Pal^*

来源：Free Radical Biology and Medicine, 2012, 52(2): 497-506.

DOI：10.1016/j.freeradbiomed.2011.11.001

• Nephropathy
• Cisplatin
• Oxidative stress
• Mitochondria
• Mitochondrial antioxidants
• Free radicals

Cisplatin is a widely used antineoplastic agent; however, its major limitation is the development of dose-dependent nephrotoxicity whose precise mechanisms are poorly understood. Here we show not only that mitochondrial dysfunction is a feature of cisplatin nephrotoxicity, but also that targeted delivery of superoxide dismutase mimetics to mitochondria largely prevents the renal effects of cisplatin. Cisplatin induced renal oxidative stress, deterioration of mitochondrial structure and function, an intense inflammatory response, histopathological injury, and renal dysfunction. A single systemic dose of mitochondrially targeted antioxidants, MitoQ or Mito-CP, dose-dependently prevented cisplatin-induced renal dysfunction. Mito-CP also prevented mitochondrial injury and dysfunction, renal inflammation, and tubular injury and apoptosis. Despite being broadly renoprotective against cisplatin, Mito-CP did not diminish cisplatin%26apos;s antineoplastic effect in a human bladder cancer cell line. Our results highlight the central role of mitochondrially generated oxidants in the pathogenesis of cisplatin nephrotoxicity. Because similar compounds seem to be safe in humans, mitochondrially targeted antioxidants may represent a novel therapeutic approach against cisplatin nephrotoxicity.

• 出版日期2012-1-15