Manganese superoxide dismutase attenuates Cisplatin-induced renal injury: importance of superoxide.
Cisplatin is a potent chemotherapeutic agent that is used to treat many human malignancies. Unfortunately, in addition to side effects such as ototoxicity, anaphylaxis, and bone marrow suppression, a significant percentage of patients receiving cisplatin develop severe nephrotoxicity. Mitochondrial dysfunction that is mediated via the generation of reactive oxygen species has been implicated in the pathogenesis of cisplatin-induced renal injury. To address the mechanism, it was hypothesized that overexpression of antioxidant enzymes, such as mitochondria-localized manganese superoxide dismutase (MnSOD) or mitochondria-targeted catalase (mito-Cat), would be cytoprotective in cisplatin-induced cell injury. To this end, human MnSOD or a mito-Cat vector were stably transfected into human embryonic kidney 293 cells. Cells that overexpressed MnSOD exhibited significantly less cell rounding and detachment compared with both mito-Cat and vector controls after exposure to 20 microM cisplatin. Cell injury as assessed by DNA fragmentation and annexin V binding assays was significantly decreased in the cells that overexpressed MnSOD compared with vector alone and mito-Cat. In addition, elevated levels of MnSOD were strongly associated with increased clonogenic potential after cisplatin challenge. Thus, overexpression of MnSOD, and not catalase, protects against cisplatin-induced renal epithelial cell injury. These results demonstrate the importance of reactive oxygen species in the mechanism that underlies cisplatin-induced renal injury and specifically implicate the superoxide radical, and not hydrogen peroxide, as the mediator.
Davis
Christopher A
CA
*Department of Biochemistry and Molecular Biology, Department of Medicine, and Department of Neuroscience, University of Florida, Gainesville, Florida.
Nick
Harry S
HS
*Department of Biochemistry and Molecular Biology, Department of Medicine, and Department of Neuroscience, University of Florida, Gainesville, Florida.
Agarwal
Anupam
A
*Department of Biochemistry and Molecular Biology, Department of Medicine, and Department of Neuroscience, University of Florida, Gainesville, Florida.
D000970:Antineoplastic Agents; D002374:Catalase / Q000235:genetics / Q000494:pharmacology; D002460:Cell Line; D002945:Cisplatin; D019610:Cytoprotection; D015870:Gene Expression; D006801:Humans; D006861:Hydrogen Peroxide; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology*; D008928:Mitochondria / Q000201:enzymology; D016877:Oxidants; D013482:Superoxide Dismutase / Q000235:genetics / Q000494:pharmacology*
D000970:Antineoplastic Agents; D016877:Oxidants; D006861:Hydrogen Peroxide; D002374:Catalase; D013482:Superoxide Dismutase; D002945:Cisplatin