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Am J Physiol Renal Physiol 293: F1282-F1291, 2007. First published August 1, 2007; doi:10.1152/ajprenal.00230.2007
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Activation and involvement of p53 in cisplatin-induced nephrotoxicity

Qingqing Wei,1 Guie Dong,1 Tianxin Yang,2 Judit Megyesi,3 Peter M. Price,3 and Zheng Dong1

1Department of Cellular Biology and Anatomy, Medical College of Georgia and Veterans Affairs Medical Center, Augusta, Georgia; 2Department of Internal Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City, Utah; and 3Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas

Submitted 17 May 2007 ; accepted in final form 27 July 2007

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.

cisplatin; nephrotoxicity; p53; apoptosis; acute kidney injury


Address for reprint requests and other correspondence: Z. Dong, Dept. of Cellular Biology and Anatomy, Medical College of Georgia, 1459 Laney Walker Blvd., Augusta, GA 30912 (e-mail: zdong{at}mail.mcg.edu)






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