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Reduction of Renal Superoxide Dismutase in Progressive Diabetic Nephropathy

Hiroki Fujita^*,, Hiromi Fujishima^*, Shinsuke Chida, Keiko Takahashi, Zhonghua Qi, Yukiko Kanetsuna, Matthew D. Breyer, Raymond C. Harris, Yuichiro Yamada^* and Takamune Takahashi

^* Division of Endocrinology, Metabolism and Geriatric Medicine, and Bioscience Education Research Center, Akita University School of Medicine, Akita, Japan; Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee; and Division of Pathology, Jikei University School of Medicine, Tokyo, Japan

Correspondence: Dr. Hiroki Fujita, Division of Endocrinology, Metabolism and Geriatric Medicine, Akita University School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan. Phone: +81-18-884-6040; Fax: +81-18-884-6449; E-mail: hirofuji{at}gipc.akita-u.ac.jp; or Dr. Takamune Takahashi, Division of Nephrology and Hypertension, Vanderbilt University Medical Center, S-3223, MCN, Nashville, Tennessee 37232. Phone: 615-343-4312; Fax: 615-343-7156; E-mail: takamune.takahashi{at}vanderbilt.edu

Received for publication August 12, 2008. Accepted for publication February 2, 2009.

Superoxide excess plays a central role in tissue damage that results from diabetes, but the mechanisms of superoxide overproduction in diabetic nephropathy (DN) are incompletely understood. In the present study, we investigated the enzyme superoxide dismutase (SOD), a major defender against superoxide, in the kidneys during the development of murine DN. We assessed SOD activity and the expression of SOD isoforms in the kidneys of two diabetic mouse models (C57BL/6-Akita and KK/Ta-Akita) that exhibit comparable levels of hyperglycemia but different susceptibility to DN. We observed down-regulation of cytosolic CuZn-SOD (SOD1) and extracellular CuZn-SOD (SOD3), but not mitochondrial Mn-SOD (SOD2), in the kidney of KK/Ta-Akita mice which exhibit progressive DN. In contrast, we did not detect a change in renal SOD expression in DN-resistant C57BL/6-Akita mice. Consistent with these findings, there was a significant reduction in total SOD activity in the kidney of KK/Ta-Akita mice compared with C57BL/6-Akita mice. Finally, treatment of KK/Ta-Akita mice with a SOD mimetic, tempol, ameliorated the nephropathic changes in KK/Ta-Akita mice without altering the level of hyperglycemia. Collectively, these results indicate that down-regulation of renal SOD1 and SOD3 may play a key role in the pathogenesis of DN.

Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673