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Expression, localization, and function of the thioredoxin system in diabetic nephropathy.

ABSTRACT: 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.

SUBMITTER: Advani A

PROVIDER: S-EPMC2663825 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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Expression, localization, and function of the thioredoxin system in diabetic nephropathy.

Advani Andrew A Gilbert Richard E RE Thai Kerri K Gow Renae M RM Langham Robyn G RG Cox Alison J AJ Connelly Kim A KA Zhang Yuan Y Herzenberg Andrew M AM Christensen Per Knud PK Pollock Carol A CA Qi Weier W Tan Sih Min SM Parving Hans-Henrik HH Kelly Darren J DJ

Journal of the American Society of Nephrology : JASN 20090211 4

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 glom ...[more]

PMID: 19211714

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Dataset Information

Expression, localization, and function of the thioredoxin system in diabetic nephropathy.

Publications

Expression, localization, and function of the thioredoxin system in diabetic nephropathy.

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