Cytoprotective effects of hypoxia against cisplatin-induced tubular cell apoptosis: involvement of mitochondrial inhibition and p53 suppression.

Wang J, Biju MP, Wang MH, Haase VH, Dong Z
J Am Soc Nephrol. 2006 17 (7): 1875-85

PMID: 16762987 · DOI:10.1681/ASN.2005121371

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 microM 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.

MeSH Terms (19)

Adenosine Triphosphate Animals Antineoplastic Agents Apoptosis bcl-2-Associated X Protein Cell Line Cells, Cultured Cisplatin Cobalt Cytoprotection Electron Transport Complex III Hypoxia Hypoxia-Inducible Factor 1 Kidney Tubules Mice Mitochondria Rats Stem Cells Tumor Suppressor Protein p53

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