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Expression, Localization, and Function of the Thioredoxin System in Diabetic Nephropathy

Andrew Advani^*, Richard E. Gilbert^*, Kerri Thai^*, Renae M. Gow, Robyn G. Langham, Alison J. Cox, Kim A. Connelly^*, Yuan Zhang, Andrew M. Herzenberg, Per Knud Christensen, Carol A. Pollock^||, Weier Qi, Sih Min Tan, Hans-Henrik Parving^¶ and Darren J. Kelly

^* Keenan Research Centre of the Li Ka Shing Knowledge Institute, St. Michael's Hospital, and Department of Pathology, University Health Network, Toronto, Ontario, Canada; Department of Medicine, St. Vincent's Hospital, University of Melbourne, Melbourne, Victoria, and ^|| Department of Medicine, Royal North Shore Hospital, New South Wales, Australia; and Steno Diabetes Center, Gentofte, and ^¶ Department of Medical Endocrinology, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark

Correspondence: Dr. Richard E. Gilbert, St. Michael's Hospital, 61 Queen Street East, Toronto, Ontario, Canada, M5C 2T2. Phone: 416-867-3747; Fax: 416-867-7495; E-mail: richard.gilbert{at}utoronto.ca

Received for publication February 6, 2008. Accepted for publication October 20, 2008.

Excessive reactive oxygen species play a key role in the pathogenesis of diabetic nephropathy, but to what extent these result from increased generation, impaired antioxidant systems, or both is incompletely understood. Here, we report the expression, localization, and activity of the antioxidant thioredoxin and its endogenous inhibitor thioredoxin interacting protein (TxnIP) in vivo and in vitro. In normal human and rat kidneys, expression of TxnIP mRNA and protein was most abundant in the glomeruli and distal nephron (distal convoluted tubule and collecting ducts). In contrast, thioredoxin mRNA and protein localized to the renal cortex, particularly within the proximal tubules and to a lesser extent in the distal nephron. Induction of diabetes in rats increased expression of TxnIP but not thioredoxin mRNA. Kidneys from patients with diabetic nephropathy had significantly higher levels of TxnIP than control kidneys, but thioredoxin expression did not differ. In vitro, high glucose increased TxnIP expression in mesangial, NRK (proximal tubule), and MDCK (distal tubule/collecting duct) cells, and decreased the expression of thioredoxin in mesangial and MDCK cells. Knockdown of TxnIP with small interference RNA suggested that TxnIP mediates the glucose-induced impairment of thioredoxin activity. Knockdown of TxnIP also abrogated both glucose-induced ³H-proline incorporation (a marker of collagen production) and oxidative stress. Taken together, these findings suggest that impaired thiol reductive capacity contributes to the generation of reactive oxygen species in diabetes in a site- and cell-specific manner.

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				A. Advani, D. J. Kelly, A. J. Cox, K. E. White, S. L. Advani, K. Thai, K. A. Connelly, D. Yuen, J. Trogadis, A. M. Herzenberg, et al. The (Pro)Renin Receptor: Site-Specific and Functional Linkage to the Vacuolar H+-ATPase in the Kidney Hypertension, August 1, 2009; 54(2): 261 - 269. [Abstract] [Full Text] [PDF]

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