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, Darren J. Kelly

Research output: Contribution to journalArticleResearchpeer-review

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 thiore- doxin 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 oxida- tive 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.

Original languageEnglish
Pages (from-to)730-741
Number of pages12
JournalJournal of the American Society of Nephrology
Volume20
Issue number4
DOIs
Publication statusPublished - Apr 2009
Externally publishedYes

Cite this

Advani, Andrew ; Gilbert, Richard E ; Thai, Kerri ; Gow, Renae M. ; Langham, Robyn G. ; Cox, Alison J. ; Connelly, Kim A. ; Zhang, Yuan ; Herzenberg, Andrew M. ; Christensen, Per Knud ; Pollock, Carol A ; Qi, Weier ; Tan, Sih Min ; Parving, Hans Henrik ; Kelly, Darren J. / Expression, localization, and function of the thioredoxin system in diabetic nephropathy. In: Journal of the American Society of Nephrology. 2009 ; Vol. 20, No. 4. pp. 730-741.
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title = "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 thiore- doxin 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 oxida- tive 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.",
author = "Andrew Advani and Gilbert, {Richard E} and Kerri Thai and Gow, {Renae M.} and Langham, {Robyn G.} and Cox, {Alison J.} and Connelly, {Kim A.} and Yuan Zhang and Herzenberg, {Andrew M.} and Christensen, {Per Knud} and Pollock, {Carol A} and Weier Qi and Tan, {Sih Min} and Parving, {Hans Henrik} and Kelly, {Darren J.}",
year = "2009",
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doi = "10.1681/ASN.2008020142",
language = "English",
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Advani, A, Gilbert, RE, Thai, K, Gow, RM, Langham, RG, Cox, AJ, Connelly, KA, Zhang, Y, Herzenberg, AM, Christensen, PK, Pollock, CA, Qi, W, Tan, SM, Parving, HH & Kelly, DJ 2009, 'Expression, localization, and function of the thioredoxin system in diabetic nephropathy' Journal of the American Society of Nephrology, vol. 20, no. 4, pp. 730-741. https://doi.org/10.1681/ASN.2008020142

Expression, localization, and function of the thioredoxin system in diabetic nephropathy. / Advani, Andrew; Gilbert, Richard E; Thai, Kerri; Gow, Renae M.; Langham, Robyn G.; Cox, Alison J.; Connelly, Kim A.; Zhang, Yuan; Herzenberg, Andrew M.; Christensen, Per Knud; Pollock, Carol A; Qi, Weier; Tan, Sih Min; Parving, Hans Henrik; Kelly, Darren J.

In: Journal of the American Society of Nephrology, Vol. 20, No. 4, 04.2009, p. 730-741.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Expression, localization, and function of the thioredoxin system in diabetic nephropathy

AU - Advani, Andrew

AU - Gilbert, Richard E

AU - Thai, Kerri

AU - Gow, Renae M.

AU - Langham, Robyn G.

AU - Cox, Alison J.

AU - Connelly, Kim A.

AU - Zhang, Yuan

AU - Herzenberg, Andrew M.

AU - Christensen, Per Knud

AU - Pollock, Carol A

AU - Qi, Weier

AU - Tan, Sih Min

AU - Parving, Hans Henrik

AU - Kelly, Darren J.

PY - 2009/4

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N2 - 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 thiore- doxin 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 oxida- tive 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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