Activation and involvement of p53 in cisplatin-induced nephrotoxicity

Qingqing Wei, Guie Dong, Tianxin Yang, Judit Megyesi, Peter M. Price, Zheng Dong

Research output: Contribution to journalArticle

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Abstract

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-α, 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.

Original languageEnglish (US)
Pages (from-to)F1282-F1291
JournalAmerican Journal of Physiology - Renal Physiology
Volume293
Issue number4
DOIs
StatePublished - Oct 1 2007

Fingerprint

Cisplatin
Wild Animals
Apoptosis
Kidney
Acute Kidney Injury
Pharmacology
Gene Knockout Techniques
Inbred C57BL Mouse
Therapeutics
Phosphorylation
Drug Therapy
Wounds and Injuries
Pharmaceutical Preparations
Neoplasms
Proteins

Keywords

  • Acute kidney injury
  • Apoptosis
  • Cisplatin
  • Nephrotoxicity
  • p53

ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this

Activation and involvement of p53 in cisplatin-induced nephrotoxicity. / Wei, Qingqing; Dong, Guie; Yang, Tianxin; Megyesi, Judit; Price, Peter M.; Dong, Zheng.

In: American Journal of Physiology - Renal Physiology, Vol. 293, No. 4, 01.10.2007, p. F1282-F1291.

Research output: Contribution to journalArticle

Wei, Qingqing ; Dong, Guie ; Yang, Tianxin ; Megyesi, Judit ; Price, Peter M. ; Dong, Zheng. / Activation and involvement of p53 in cisplatin-induced nephrotoxicity. In: American Journal of Physiology - Renal Physiology. 2007 ; Vol. 293, No. 4. pp. F1282-F1291.
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