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

Heme oxygenase-l (HO-1) is a 32-kDa microsomal enzyme that catalyzes the co nversion of heme to biliverdin, releasing iron and carbon monoxide. Inducti on of HO-1 occurs as a protective response in cells/tissues exposed to a wi de variety of oxidant stimuli. The chemotherapeutic effects of cis-diammine dichloroplatinum(II) (cisplatin), a commonly used anticancer drug, are limi ted by significant nephrotoxicity, which is characterized by varying degree s of renal tubular apoptosis and necrosis. The purpose of this study was to evaluate the functional significance of HO-1 expression in cisplatin-induc ed renal injury. Our studies demonstrate that transgenic mice deficient in HO-1 (-/-), develop more severe renal failure and have significantly greate r renal injury compared with wild-type (+/+) mice treated with cisplatin. I n 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 cytop rotective effect. Overexpression of HO-1 resulted in a significant reductio n in cisplatin-induced cytotoxicity. These studies provide a basis for futu re studies using targeted gene expression of HO-1 as a therapeutic and prev entive modality in high-risk settings of acute renal failure.