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NDT Advance Access published online on September 8, 2009
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfp454
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© The Author 2009. Published by Oxford University Press [on behalf of ERA-EDTA]. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Activation of hypoxia-inducible factor attenuates renal injury in rat remnant kidney

Young Rim Song1, Sun Jin You2, Yun-Mi Lee2, Ho Joon Chin2,3, Dong-Wan Chae2,3, Yun Kyu Oh3, Kwon Wook Joo3, Jin Suk Han3 and Ki Young Na2,3

1 Department of Internal Medicine and Kidney Research Institute, Hallym University College of Medicine, Anyang 2 Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam 3 Seoul National University College of Medicine, Seoul, Korea

Correspondence and offprint requests to: Ki Young Na; E-mail: kyna{at}snubh.org



  Abstract

Background. Chronic hypoxia in the kidney has been suggested as a final common pathway to end-stage renal disease. Hypoxia-inducible factor (HIF) is a transcription factor that regulates cellular hypoxic responses, and it is a promising target with therapeutic potential in various kidney disease models. In this study, we investigated whether HIF activation could attenuate renal injury in the rat remnant kidney model.

Methods. Two weeks after a subtotal nephrectomy, rats received a continuous infusion of dimethyloxalylglycine (DMOG) for 4 weeks to activate HIF.

Results. The DMOG infusion halted the progression of proteinuria. A histological evaluation revealed that the glomerulosclerosis and tubulointerstitial injury were significantly decreased by DMOG treatment. DMOG increased renal HIF-1{alpha} protein. The expression of glucose transporter-1 (GLUT-1) and prolyl hydroxylase 3 (PHD3) and the immunostaining of vascular endothelial growth factor (VEGF) were increased by DMOG. DMOG-treated rats showed less podocyte injury manifested by decreased immunostaining of desmin and the restoration of podoplanin staining. Furthermore, plasma malondialdehyde (MDA), a marker of oxidative stress, showed a tendency to decrease, and the renal expression of catalase, an antioxidant, was significantly increased by DMOG. The DMOG treatment decreased macrophage infiltration and reduced fibrosis, as manifested by decreased type IV collagen and osteopontin expression.

Conclusions. Activation of HIF by DMOG halted the progression of proteinuria and attenuated structural damage by preventing podocyte injury in the remnant kidney model. This renoprotection was accompanied by a reduction of oxidative stress, inflammation and fibrosis.

Keywords: DMOG (dimethyloxalylglycine); fibrosis; inflammation; oxidative stress; podocyte injury

Received for publication: 25.12.08
Accepted in revised form: 11. 8.09


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