Activation and involvement of p53 in cisplatin-induced nephrotoxicity
Open Access
- 1 October 2007
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Renal Physiology
- Vol. 293 (4), F1282-F1291
- https://doi.org/10.1152/ajprenal.00230.2007
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.Keywords
This publication has 48 references indexed in Scilit:
- Effects of hydroxyl radical scavenging on cisplatin-induced p53 activation, tubular cell apoptosis and nephrotoxicityBiochemical Pharmacology, 2007
- p53 in health and diseaseNature Reviews Molecular Cell Biology, 2007
- Nutlin-3 Protects Kidney Cells during Cisplatin Therapy by Suppressing Bax/Bak ActivationOnline Journal of Public Health Informatics, 2007
- Caspase-mediated cleavage of ATM during cisplatin-induced tubular cell apoptosis: inactivation of its kinase activity toward p53American Journal of Physiology-Renal Physiology, 2006
- p53-dependent Caspase-2 Activation in Mitochondrial Release of Apoptosis-inducing Factor and Its Role in Renal Tubular Epithelial Cell InjuryOnline Journal of Public Health Informatics, 2005
- White adipose tissue sensory nerve denervation mimics lipectomy-induced compensatory increases in adiposityAmerican Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2005
- Prospective therapeutic applications of p53 inhibitorsBiochemical and Biophysical Research Communications, 2005
- Cellular processing of platinum anticancer drugsNature Reviews Drug Discovery, 2005
- Delayed DMSO Administration Protects the Kidney from Mercuric Chloride-Induced InjuryJournal of the American Society of Nephrology, 2004
- Cisplatin: mode of cytotoxic action and molecular basis of resistanceOncogene, 2003