Activation and involvement of p53 in cisplatin-induced nephrotoxicity
Activation and involvement of p53 in cisplatin-induced nephrotoxicity
复制标题
DOI：
10.1152/ajprenal.00230.2007
复制
发表时间：
2007-10-01
影响因子：
4.2
通讯作者：
Dong, Zheng
中科院分区：
文献类型：
--
作者：
Wei, Qingqing;Dong, Guie;Dong, Zheng
顺铂是一种广泛使用的化疗药物，可引起急性肾损伤，这限制了其在癌症治疗中的使用和疗效。然而，顺铂引起肾毒性的分子机制目前尚不清楚。利用药理学和基因敲除模型，我们现在证明了 p53 在顺铂肾毒性中的病理作用。在 C57BL/6 小鼠中，顺铂治疗诱导 p53 磷酸化和蛋白质积累，并伴有急性肾损伤的发生。 p53 在近端和远端肾小管细胞中均被诱导，并且部分与细胞凋亡共定位。 Pifithrin-alpha 是 p53 的药理学抑制剂，在顺铂治疗期间可抑制 p53 激活并改善肾损伤。此外，在 p53 缺陷小鼠中，顺铂诱导的肾毒性被消除。与野生型动物相比，p53缺陷小鼠表现出更好的肾功能、更少的组织损伤和更少的凋亡细胞。此外，与来自野生型动物的细胞相比，顺铂在从 p53 缺陷小鼠中分离的近端肾小管细胞中诱导的细胞凋亡较少。这些结果共同表明 p53 参与顺铂诱导的肾细胞凋亡和肾毒性。
Cisplatin, a widely used chemotherapy drug, induces acute kidney injury, which limits its use and efficacy in cancer treatment. However, the molecular mechanism of cisplatin-induced nephrotoxicity is currently unclear. Using pharmacological and gene knockout models, we now demonstrate a pathological role for p53 in cisplatin nephrotoxicity. In C57BL/6 mice, cisplatin treatment induced p53 phosphorylation and protein accumulation, which was accompanied by the development of acute kidney injury. p53 was induced in both proximal and distal tubular cells and partially colocalized with apoptosis. Pifithrin-alpha, a pharmacological inhibitor of p53, suppressed p53 activation and ameliorated kidney injury during cisplatin treatment. Moreover, cisplatin-induced nephrotoxicity was abrogated in p53-deficient mice. Compared with wild-type animals, p53-deficient mice showed a better renal function, less tissue damage, and fewer apoptotic cells. In addition, cisplatin induced less apoptosis in proximal tubular cells isolated from p53-deficient mice than the cells from wild-type animals. Together these results suggest the involvement of p53 in cisplatin-induced renal cell apoptosis and nephrotoxicity.