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Am J Physiol Renal Physiol 278: F726-F736, 2000;
0363-6127/00 $5.00
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Vol. 278, Issue 5, F726-F736, May 2000

Heme oxygenase-1 gene ablation or expression modulates cisplatin-induced renal tubular apoptosis

Fumie Shiraishi1, Lisa M. Curtis1, Leigh Truong1, Kenneth Poss2, Gary A. Visner3, Kirsten Madsen1, Harry S. Nick1,4, and Anupam Agarwal1

1 Department of Medicine, Division of Nephrology, Hypertension and Transplantation, 4 Department of Neuroscience, and 3 Department of Pediatrics, University of Florida, Gainesville, Florida 32610; and 2 Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139

Heme oxygenase-1 (HO-1) is a 32-kDa microsomal enzyme that catalyzes the conversion of heme to biliverdin, releasing iron and carbon monoxide. Induction of HO-1 occurs as a protective response in cells/tissues exposed to a wide variety of oxidant stimuli. The chemotherapeutic effects of cis-diamminedichloroplatinum(II) (cisplatin), a commonly used anticancer drug, are limited by significant nephrotoxicity, which is characterized by varying degrees of renal tubular apoptosis and necrosis. The purpose of this study was to evaluate the functional significance of HO-1 expression in cisplatin-induced renal injury. Our studies demonstrate that transgenic mice deficient in HO-1 (-/-), develop more severe renal failure and have significantly greater renal injury compared with wild-type (+/+) mice treated with cisplatin. In vitro studies in human renal proximal tubule cells demonstrate that hemin, an inducer of HO-1, significantly attenuated cisplatin-induced apoptosis and necrosis, whereas inhibition of HO-1 enzyme activity reversed the cytoprotective effect. Overexpression of HO-1 resulted in a significant reduction in cisplatin-induced cytotoxicity. These studies provide a basis for future studies using targeted gene expression of HO-1 as a therapeutic and preventive modality in high-risk settings of acute renal failure.

acute renal failure; oxidative stress; cytoprotection; carbon monoxide; cancer chemotherapy


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