Mitochondrial-targeted antioxidants represent a promising approach for prevention of cisplatin-induced nephropathy.
Mitochondrial-targeted antioxidants represent a promising approach for prevention of cisplatin-induced nephropathy.
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DOI：
10.1016/j.freeradbiomed.2011.11.001
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发表时间：
2012-01-15
影响因子：
7.4
通讯作者：
Pacher, Pal
中科院分区：
文献类型：
--
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
顺铂是一种广泛使用的抗肿瘤药物;然而，其主要局限性是剂量依赖性肾毒性的发展，其确切机制知之甚少。在这里，我们表明，线粒体功能障碍不仅是顺铂肾毒性的一个特点，但有针对性的交付超氧化物歧化酶模拟线粒体在很大程度上防止顺铂的肾脏影响。顺铂诱导肾脏氧化应激、线粒体结构和功能恶化、强烈的炎症反应、组织病理学损伤和肾功能障碍。单次全身剂量的靶向抗氧化剂MitoQ或Mito-CP可剂量依赖性地预防顺铂诱导的肾功能不全。Mito-CP还防止线粒体损伤和功能障碍、肾脏炎症以及肾小管损伤和细胞凋亡。尽管对顺铂具有广泛的肾保护作用，但Mito-CP在人膀胱癌细胞系中并未减弱顺铂的抗肿瘤作用。我们的研究结果突出了中枢神经系统产生的氧化剂在顺铂肾毒性的发病机制中的作用。由于类似的化合物似乎在人体内是安全的，因此靶向抗氧化剂可能代表了一种新的治疗顺铂肾毒性的方法。
Cisplatin is a widely used anti-neoplastic agent; however, its major limitation is the development of dose-dependent nephrotoxicity whose precise mechanisms are poorly understood. Here we show that mitochondrial dysfunction is not only a feature of cisplatin nephrotoxicity, but 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’s anti-neoplastic effect in a human bladder cancer cell line. Our results highlight the central role of mitochondrially generated oxidants in the pathogenesis of cisplatin nephrotoxicity. Since similar compounds appear to be safe in humans, mitochondrially-targeted antioxidants may represent a novel therapeutic approach against cisplatin nephrotoxicity.
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影响因子：
7.4
作者：
Mukhopadhyay, Partha;Rajesh, Mohanraj;Pan, Hao;Patel, Vivek;Mukhopadhyay, Bani;Batkai, Sandor;Gao, Bin;Hasko, Gyoergy;Pacher, Pal
通讯作者：
Pacher, Pal
影响因子：
13.6
作者：
Davis, CA;Nick, HS;Agarwal, A
通讯作者：
Agarwal, A
DOI：
10.1152/ajprenal.00206.2004
发表时间：
2004-11-01
影响因子：
4.2
作者：
Li, SY;Bhatt, R;Portilla, D
通讯作者：
Portilla, D
影响因子：
5.3
作者：
Cassina, Patricia;Cassina, Adriana;Radi, Rafael
通讯作者：
Radi, Rafael
影响因子：
19.6
作者：
Deng, JP;Kohda, Y;Star, RA
通讯作者：
Star, RA