Manganese superoxide dismutase attenuates cisplatin-induced renal injury: Importance of superoxide
Manganese superoxide dismutase attenuates cisplatin-induced renal injury: Importance of superoxide
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DOI：
10.1681/asn.v12122683
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发表时间：
2001-12-01
影响因子：
13.6
通讯作者：
Agarwal, A
中科院分区：
文献类型：
--
作者：
Davis, CA;Nick, HS;Agarwal, A
顺铂是一种有效的化学治疗剂，用于治疗许多人类恶性肿瘤。不幸的是，除了耳毒性、过敏反应和骨髓抑制等副作用外，接受顺铂治疗的患者中有很大比例发生严重的肾毒性。线粒体功能障碍是通过产生活性氧介导的，这与顺铂诱导的肾损伤的发病机制有关。为了解决机制，假设过表达抗氧化酶，如α-定位的锰超氧化物歧化酶（MnSOD）或α-靶向的过氧化氢酶（mito-Cat），将在顺铂诱导的细胞损伤中具有细胞保护作用。为此，将人MnSOD或mito-Cat载体稳定转染到人胚肾293细胞中。在暴露于20 μ M顺铂后，与mito-Cat和载体对照相比，过表达MnSOD的细胞表现出显著更少的细胞变圆和分离。通过DNA片段化和膜联蛋白V结合试验评估的细胞损伤显着降低的细胞，过表达MnSOD相比，单独的载体和mito-Cat。此外，MnSOD水平升高与顺铂挑战后的克隆形成潜力增加密切相关。因此，MnSOD的过度表达，而不是过氧化氢酶，保护顺铂诱导的肾上皮细胞损伤。这些结果表明活性氧在顺铂诱导的肾损伤机制中的重要性，特别是涉及超氧自由基，而不是过氧化氢，作为介体。
Cisplatin is a potent chemotherapeutic agent that is used to treat many human malignancies. Unfortunately, in addition to side effects such as ototoxicity, anaphylaxis, and bone marrow suppression, a significant percentage of patients receiving cisplatin develop severe nephrotoxicity. Mitochondrial dysfunction that is mediated via the generation of reactive oxygen species has been implicated in the pathogenesis of cisplatin-induced renal injury. To address the mechanism, it was hypothesized that overexpression of antioxidant enzymes, such as mitochondria-localized manganese superoxide dismutase (MnSOD) or mitochondria-targeted catalase (mito-Cat), would be cytoprotective in cisplatin-induced cell injury. To this end, human MnSOD or a mito-Cat vector were stably transfected into human embryonic kidney 293 cells. Cells that overexpressed MnSOD exhibited significantly less cell rounding and detachment compared with both mito-Cat and vector controls after exposure to 20 muM cisplatin. Cell injury as assessed by DNA fragmentation and annexin V binding assays was significantly decreased in the cells that overexpressed MnSOD compared with vector alone and mito-Cat. In addition, elevated levels of MnSOD were strongly associated with increased clonogenic potential after cisplatin challenge. Thus, overexpression of MnSOD, and not catalase, protects against cisplatin-induced renal epithelial cell injury. These results demonstrate the importance of reactive oxygen species in the mechanism that underlies cisplatin-induced renal injury and specifically implicate the superoxide radical, and not hydrogen peroxide, as the mediator.