Wei Qingqing, Dong Guie, Yang Tianxin, Megyesi Judit, Price Peter M, Dong Zheng
Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta, GA 30912, USA.
Am J Physiol Renal Physiol. 2007 Oct;293(4):F1282-91. doi: 10.1152/ajprenal.00230.2007. Epub 2007 Aug 1.
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.
顺铂是一种广泛使用的化疗药物，可引发急性肾损伤，这限制了其在癌症治疗中的应用及疗效。然而，目前顺铂所致肾毒性的分子机制尚不清楚。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，顺铂治疗诱导了p53磷酸化和蛋白积累，同时伴有急性肾损伤的发展。p53在近端和远端肾小管细胞中均被诱导，并部分与凋亡共定位。p53的药理学抑制剂Pifithrin-α可抑制p53激活，并改善顺铂治疗期间的肾损伤。此外，顺铂诱导的肾毒性在p53基因缺陷小鼠中被消除。与野生型动物相比，p53基因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，与野生型动物来源的细胞相比，顺铂诱导p53基因缺陷小鼠分离的近端肾小管细胞发生的凋亡更少。这些结果共同表明p53参与了顺铂诱导的肾细胞凋亡和肾毒性。
