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This Article Full Text Full Text (PDF) All Versions of this Article: 296/3/F622    most recent 90566.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kim, J. Articles by Park, K. M. Search for Related Content PubMed PubMed Citation Articles by Kim, J. Articles by Park, K. M.

Role of cytosolic NADP⁺-dependent isocitrate dehydrogenase in ischemia-reperfusion injury in mouse kidney

¹Department of Anatomy and BK 21 Project, Kyungpook National University School of Medicine, Daegu, Republic of Korea; ²Department of Medicine IV, Tokyo Women's Medical University, Tokyo, Japan; ³School of Life Sciences and Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea; and ⁴Renal Division, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, Massachusetts

Submitted 22 September 2008 ; accepted in final form 18 December 2008

Cytosolic NADP⁺-dependent isocitrate dehydrogenase (IDPc) synthesizes reduced NADP (NADPH), which is an essential cofactor for the generation of reduced glutathione (GSH), the most abundant and important antioxidant in mammalian cells. We investigated the role of IDPc in kidney ischemia-reperfusion (I/R) in mice. The activity and expression of IDPc were highest in the cortex, modest in the outer medulla, and lowest in the inner medulla. NADPH levels were greatest in the cortex. IDPc expression in the S1 and S2 segments of proximal tubules was higher than in the S3 segment, which is much more susceptible to I/R. IDPc protein was also highly expressed in the mitochondrion-rich intercalated cells of the collecting duct. IDPc activity was 10- to 30-fold higher than the activity of glucose-6-phosphate dehydrogenase, another producer of cytosolic NADPH, in various kidney regions. This study identifies that IDPc may be the primary source of NADPH in the kidney. I/R significantly reduced IDPc expression and activity and NADPH production and increased the ratio of oxidized glutathione to total glutathione [GSSG/(GSH+GSSG)], resulting in kidney dysfunction, tubular cell damage, and lipid peroxidation. In LLC-PK₁ cells, upregulation of IDPc by IDPc gene transfer protected the cells against hydrogen peroxide, enhancing NADPH production, inhibiting the increase of GSSG/(GSH+GSSG), and reducing lipid peroxidation. IDPc downregulation by small interference RNA treatment presented results contrasting with the upregulation. In conclusion, these results demonstrate that IDPc is expressed differentially along tubules in patterns that may contribute to differences in susceptibility to injury, is a major enzyme in cytosolic NADPH generation in kidney, and is downregulated with I/R.

reduced nicotinamide adenine dinucleotide phosphate; glutathione; proximal tubular cell; acute kidney injury; oxidative stress; ROS

This article has been cited by other articles:

				J. Kim, Y. M. Seok, K.-J. Jung, and K. M. Park Reactive oxygen species/oxidative stress contributes to progression of kidney fibrosis following transient ischemic injury in mice Am J Physiol Renal Physiol, August 1, 2009; 297(2): F461 - F470. [Abstract] [Full Text] [PDF]

				J. Kim, J.-W. Park, and K. M. Park Increased superoxide formation induced by irradiation preconditioning triggers kidney resistance to ischemia-reperfusion injury in mice Am J Physiol Renal Physiol, May 1, 2009; 296(5): F1202 - F1211. [Abstract] [Full Text] [PDF]