Differential roles of hydrogen peroxide and hydroxyl radical in cisplatin-induced cell death in renal proximal tubular epithelial cells
Differential roles of hydrogen peroxide and hydroxyl radical in cisplatin-induced cell death in renal proximal tubular epithelial cells
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DOI：
10.1016/s0022-2143(03)00111-2
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发表时间：
2003-09-01
期刊：
影响因子：
--
通讯作者：
Kim, YK
中科院分区：
文献类型：
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作者：
Baek, SM;Kwon, CH;Kim, YK
活性氧（ROS）被认为是体内顺铂诱导的急性肾功能衰竭的重要介质。然而，我们以前的研究表明，顺铂诱导的细胞死亡在体外不能阻止过氧化氢和羟自由基清除剂在兔肾皮质切片。这种差异可能归因于ROS在坏死和凋亡细胞死亡中的不同作用。因此，在这项研究中，我们研究了活性氧在顺铂诱导的原代培养的兔近端小管坏死和凋亡中的作用。顺铂在高浓度下在几个小时内诱导坏死，在低得多的浓度下在更长的时间内诱导凋亡。高浓度顺铂诱导的坏死被细胞可渗透的超氧化物清除剂（铁），过氧化氢清除剂（过氧化氢酶和丙酮酸盐），和抗氧化剂（Trolox和去铁胺），而羟基自由基清除剂（二甲基硫脲和硫脲）没有影响顺铂诱导的坏死。然而，由较低浓度的顺铂诱导的细胞凋亡，部分阻止由铁和羟基自由基清除剂，但不是由过氧化氢清除剂和抗氧化剂。顺铂诱导的细胞凋亡是通过与线粒体释放细胞色素c和caspase-3激活相关的信号通路介导的。这些影响被阻止由铁和二甲基硫脲，但不是由过氧化氢酶。二甲基硫脲对顺铂诱导的急性肾功能衰竭有显著的保护作用，其作用与抑制细胞凋亡有关。这些结果表明，过氧化氢参与了顺铂诱导的坏死，而羟基自由基是负责顺铂诱导的凋亡。羟自由基清除剂的保护作用与抑制细胞色素c释放和半胱天冬酶激活有关。
Reactive oxygen species (ROS) have been suggested as important mediators of cisplatin-induced acute renal failure in vivo. However, our previous studies have shown that cisplatin-induced cell death in vitro could not be prevented by scavengers of hydrogen peroxide and hydroxyl radical in rabbit renal cortical slices. This discrepancy may be attributed to differential roles of ROS in necrotic and apoptotic cell death. We therefore examined, in this study, the roles of ROS in necrosis and apoptosis induced by cisplatin in primary cultured rabbit proximal tubule. Cisplatin induced necrosis at high concentrations over a few hours and apoptosis at much lower concentrations over longer periods. Necrosis induced by high concentration of cisplatin was prevented by a cell-permeable superoxide scavenger (tiron), hydrogen peroxide scavengers (catalase and pyruvate), and antioxidants (Trolox and deferoxamine), whereas hydroxyl radical scavengers (dimethythiourea and thiourea) did not affect the cisplatin-induced necrosis. However, apoptosis induced by lower concentration of cisplatin was partially prevented by tiron and hydroxyl radical scavengers but not by hydrogen peroxide scavengers and antioxidants. Cisplatin-induced apoptosis was mediated by the signaling pathway that is associated with cytochrome c release from mitochondria and caspase-3 activation. These effects were prevented by tiron and dimethylthiourea but not by catalase. Dimethylthiourea produced a significant protection against cisplatin-induced acute renal failure, and the effect was associated with an inhibition of apoptosis. These results suggest that hydrogen peroxide is involved in the cisplatin-induced necrosis, whereas hydroxyl radical is responsible for the cisplatin-induced apoptosis. The protective effects of hydroxyl radical scavengers are associated with an inhibition of cytochrome c release and caspase activation.