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This Article Full Text Full Text (PDF) All Versions of this Article: 296/5/F983    most recent 90579.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Jiang, M. Articles by Dong, Z. Search for Related Content PubMed PubMed Citation Articles by Jiang, M. Articles by Dong, Z.

Cisplatin-induced apoptosis in p53-deficient renal cells via the intrinsic mitochondrial pathway

¹Department of Cellular Biology and Anatomy, ²Center for Biotechnology and Genomic Medicine, and ³Department of Biochemistry and Molecular Biology, Medical College of Georgia and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia; and ⁴Department of Internal Medicine, University of Utah, Salt Lake City, Utah

Submitted 26 September 2008 ; accepted in final form 5 March 2009

Nephrotoxicity is the major limiting factor for the use of cisplatin in cancer therapy. Recent studies have demonstrated an important role for p53 in cisplatin-induced renal injury. Nevertheless, pharmacological and genetic blockade of p53 only provides partial renoprotective effects, suggesting the presence of p53-independent injury mechanisms. To understand the p53-independent mechanisms, we have now examined cisplatin-induced apoptosis in p53-deficient kidney cells. We show that cisplatin could induce Bax activation, cytochrome c release, and apoptosis in primary cultures of p53-deficient renal tubular cells, albeit at a level that was lower than in the wild-type cells. Cisplatin could also induce typical apoptosis in p53-deficient baby mouse kidney (BMK) cells. The apoptosis was caspase dependent and could be completely blocked by general caspase inhibitors. Bax and Bak, two key molecules in the mitochondrial pathway of apoptosis, were interdependently activated by cisplatin, with Bax translocation to and Bax/Bak oligomerization in mitochondria, leading to cytochrome c release. Importantly, cytochrome c release and apoptosis were diminished in Bax/Bak single or double-knockout BMK cells. Furthermore, overexpression of Bcl-2 could ameliorate cisplatin-induced cytochrome c release and apoptosis. Together, the results have demonstrated a p53-independent mechanism of cisplatin nephrotoxicity that involves the mitochondrial pathway of apoptosis.

Bax; Bak; cytochrome c