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

• Published in: Nephrology, dialysis, transplantation Vol. 25; no. 1; pp. 77 - 85
• Main Authors: Song, Young Rim, You, Sun Jin, Lee, Yun-Mi, Chin, Ho Joon, Chae, Dong-Wan, Oh, Yun Kyu, Joo, Kwon Wook, Han, Jin Suk, Na, Ki Young
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.01.2010
• Subjects: Amino Acids, Dicarboxylic - pharmacology; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Biological and medical sciences; Chronic Disease; Disease Models, Animal; Disease Progression; DMOG (dimethyloxalylglycine); Emergency and intensive care: renal failure. Dialysis management; fibrosis; Glucose Transporter Type 1 - metabolism; Hypoxia-Inducible Factor 1 - metabolism; inflammation; Intensive care medicine; Kidney - drug effects; Kidney - metabolism; Kidney - surgery; Kidney Diseases - metabolism; Kidney Diseases - physiopathology; Male; Medical sciences; Nephrectomy; Oxidative Stress; podocyte injury; Rats; Rats, Sprague-Dawley; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Surgery of the urinary system; Vascular Endothelial Growth Factor A - metabolism; fibrosis; DMOG (dimethyloxalylglycine); inflammation; podocyte injury; oxidative stress; Kidney disease; Oxidative stress; Oxygen; Urinary system disease; Rat; Hemodialysis; Rodentia; Inflammation; Podocyte; Extrarenal dialysis; Vertebrata; Mammalia; Animal; Fibrosis; Renal failure; Hypoxia
• ISSN: 0931-0509; 1460-2385
• DOI: 10.1093/ndt/gfp454

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-1α 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.