Upregulation of cytosolic NADP+-dependent isocitrate dehydrogenase by hyperglycemia protects renal cells against oxidative stress |
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Authors: | Soh-Hyun Lee Sun-Ok Ha Ho-Jin Koh KilSoo Kim Seon-Min Jeon Myung-Sook Choi Oh-Shin Kwon Tae-Lin Huh |
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Institution: | (1) School of Life Sciences and Biotechnology, College of Natural Sciences, Kyungpook National University, Taegu, 702-701, Korea;(2) Ajou University Medical School, Suwon, 442-749, Korea;(3) Keimyung University Medical School, Taegu, 700-712, Korea; |
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Abstract: | Hyperglycemia-induced oxidative stress is widely recognized as a key mediator in the pathogenesis of diabetic nephropathy,
a complication of diabetes. We found that both expression and enzymatic activity of cytosolic NADP+-dependent isocitrate dehydrogenase (IDPc) were upregulated in the renal cortexes of diabetic rats and mice. Similarly, IDPc
was induced in murine renal proximal tubular OK cells by high hyperglycemia, while it was abrogated by co-treatment with the
antioxidant N-Acetyl-Cysteine (NAC). In OK cells, increased expression of IDPc by stable transfection prevented hyperglycemia-mediated
reactive oxygen species (ROS) production, subsequent cellular oxidative stress and extracellular matrix accumulation, whereas
these processes were all stimulated by decreased IDPc expression. In addition, production of NADPH and GSH in the cytosol
was positively correlated with the expression level of IDPc in OK cells. These results together indicate that upregulation
of IDPc in response to hyperglycemia might play an essential role in preventing the progression of diabetic nephropathy, which
is accompanied by ROS-induced cellular damage and fibrosis, by providing NADPH, the reducing equivalent needed for recycling
reduced glutathione and low molecular weight antioxidant thiol proteins. |
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