Omi/HtrA2 protease mediates cisplatin-induced cell death in renal cells
Omi/HtrA2 protease mediates cisplatin-induced cell death in renal cells
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DOI：
10.1152/ajprenal.00154.2004
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发表时间：
2005-02-01
影响因子：
4.2
通讯作者：
Zervos, AS
中科院分区：
文献类型：
--
作者：
Cilenti, L;Kyriazis, GA;Zervos, AS
Omi/HtrA2是一种线粒体促凋亡丝氨酸蛋白酶，能够诱导caspase依赖性和caspase非依赖性细胞死亡。在凋亡刺激后，Omi被释放到细胞质中，在那里它结合并切割凋亡蛋白抑制剂。在本报告中，我们研究了Omi在顺铂治疗后肾细胞死亡中的作用。使用原代小鼠近端小管细胞以及已建立的肾细胞系，我们发现顺铂治疗后Omi蛋白水平上调。这种上调随后是Omi从线粒体释放到细胞质和XIAP的降解。利用RNA干扰降低内源性Omi蛋白水平可使肾细胞抵抗顺铂诱导的细胞死亡。此外，我们发现Omi的蛋白水解活性对于顺铂诱导的细胞死亡是必要的。当肾细胞用Omi的特异性抑制剂ucf-101处理时，它们对顺铂诱导的细胞死亡具有明显的耐药性。Ucf-101还能最大限度地减少动物顺铂引起的肾毒性损伤。我们的研究结果表明，Omi是顺铂诱导肾细胞死亡的主要介质，并提出了一种通过特异性抑制其蛋白水解活性来限制肾损伤的方法。
Omi/HtrA2 is a mitochondrial proapoptotic serine protease that is able to induce both caspase-dependent and caspase-independent cell death. After apoptotic stimuli, Omi is released to the cytoplasm where it binds and cleaves inhibitor of apoptosis proteins. In this report, we investigated the role of Omi in renal cell death following cisplatin treatment. Using primary mouse proximal tubule cells, as well as established renal cell lines, we show that the level of Omi protein is upregulated after treatment with cisplatin. This upregulation is followed by the release of Omi from mitochondria to the cytoplasm and degradation of XIAP. Reducing the endogenous level of Omi protein using RNA interference renders renal cells resistant to cisplatin-induced cell death. Furthermore, we show that the proteolytic activity of Omi is necessary and essential for cisplatin-induced cell death in this system. When renal cells are treated with Omi's specific inhibitor, ucf-101, they become significantly resistant to cisplatin-induced cell death. Ucf-101 was also able to minimize cisplatin-induced nephrotoxic injury in animals. Our results demonstrate that Omi is a major mediator of cisplatin-induced cell death in renal cells and suggest a way to limit renal injury by specifically inhibiting its proteolytic activity.