Upregulation of cytosolic NADP+-dependent isocitrate dehydrogenase by hyperglycemia protects renal cells against oxidative stress.
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.
Lee
Soh-Hyun
SH
School of Life Sciences and Biotechnology, Kyungpook National University, Daegu, 702-701, Korea.
Ha
Sun-Ok
SO
Koh
Ho-Jin
HJ
Kim
KilSoo
K
Jeon
Seon-Min
SM
Choi
Myung-Sook
MS
Kwon
Oh-Shin
OS
Huh
Tae-Lin
TL
D000818:Animals; D002460:Cell Line; D019610:Cytoprotection / Q000187:drug effects; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology*; D003928:Diabetic Nephropathies / Q000201:enzymology; D004285:Dogs; D004790:Enzyme Induction / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D006943:Hyperglycemia / Q000201:enzymology* / Q000473:pathology; D007521:Isocitrate Dehydrogenase / Q000096:biosynthesis / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects
D017382:Reactive Oxygen Species; D009249:NADP; D007521:Isocitrate Dehydrogenase; D005947:Glucose