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Manganese Superoxide Dismutase Attenuates Cisplatin-Induced Renal Injury: Importance of Superoxide

Christopher A. Davis^*, Harry S. Nick and Anupam Agarwal^*

*Department of Biochemistry and Molecular Biology, Department of Medicine, and Department of Neuroscience, University of Florida, Gainesville, Florida.

Correspondence to Dr. Anupam Agarwal, Assistant Professor of Medicine, Division of Nephrology, Hypertension, and Transplantation, Box 100224 JHMHC, 1600 SW Archer Road, University of Florida, Gainesville, FL 32610. Phone: 352-392-4008; Fax: 352-392-3581; E-mail: agarwal{at}nersp.nerdc.ufl.edu

ABSTRACT. 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 µM 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.

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