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Cytoprotective Effects of Hypoxia against Cisplatin-Induced Tubular Cell Apoptosis: Involvement of Mitochondrial Inhibition and p53 Suppression

Jinzhao Wang^*, Mangatt P. Biju, Mong-Heng Wang^*, Volker H. Haase and Zheng Dong^*,

^* Departments of Cellular Biology and Anatomy, and Physiology, Medical College of Georgia; Medical Research Service, Department of Veterans Affairs Medical Center, Augusta, Georgia; and Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Address correspondence to: Dr. Zheng Dong, Department of Cellular Biology and Anatomy, Medical College of Georgia, 1459 Laney Walker Boulevard, Augusta, GA 30912. Phone: 706-721-2825; Fax: 706-721-6120; zdong{at}mail.mcg.edu

Received for publication December 27, 2005. Accepted for publication April 20, 2006.

Hypoxia that is caused by vascular defects or disruption is commonly associated with renal diseases. During cisplatin nephrotoxicity, hypoxic regions are identified in the outer medulla and the renal cortex. However, the regulation of cisplatin injury by hypoxia is unclear. Previous work has demonstrated the cytoprotective effects of hypoxia against apoptotic injury. This study further examines the cytoprotective mechanisms in models of cisplatin-induced tubular cell apoptosis. In cultured renal tubular cells, 20 µM cisplatin induced approximately 60% apoptosis within 16 h. The rate of apoptosis was suppressed to <20%, when the incubation was conducted under hypoxia (2% O₂). Mitochondrial events of apoptosis, namely Bax accumulation and cytochrome c release, also were ameliorated. During cisplatin treatment, cell ATP was maintained in both normoxic and hypoxic cells. Hypoxic incubation lowered extracellular pH, but prevention of the pH decrease did not restore cisplatin-induced apoptosis. The cytoprotective effects of hypoxia also were independent of hypoxia-inducible factor 1 (HIF-1). Cobalt, as hypoxia, activated HIF-1 yet did not suppress cisplatin-induced apoptosis. Moreover, hypoxia suppressed cisplatin-induced apoptosis in HIF-1–deficient mouse embryonic stem cells and renal proximal tubular cells. Conversely, mitochondrial inhibitors, particularly inhibitors of respiration complex III (antimycin A and myxothiazol), mimicked hypoxia in apoptosis suppression. The effects of hypoxia and mitochondrial inhibitors were not additive. It is interesting that both hypoxia and complex III inhibitors ameliorated cisplatin-induced p53 activation. Therefore, the cytoprotective effects of hypoxia are independent of changes in cell ATP, pH, or HIF but may involve mitochondrial inhibition and the suppression of p53.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673