Stable expression of HIF-1alpha in tubular epithelial cells promotes interstitial fibrosis

• Published in: American journal of physiology. Renal physiology 2008-10, Vol.295 (4), p.F1023
• Main Authors: Kimura, Kuniko, Iwano, Masayuki, Higgins, Debra F, Yamaguchi, Yukinari, Nakatani, Kimihiko, Harada, Koji, Kubo, Atsushi, Akai, Yasuhiro, Rankin, Erinn B, Neilson, Eric G, Haase, Volker H, Saito, Yoshihiko
• Format: Article
• Language: English
• Subjects: Aging - pathology; Aging - physiology; Animals; Disease Models, Animal; Enzyme Activators - pharmacology; Epithelial Cells - pathology; Epithelial Cells - physiology; Female; Fibrosis; Gene Deletion; Gene Expression - physiology; Hypoxia - pathology; Hypoxia - physiopathology; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Indazoles - pharmacology; Kidney Diseases - drug therapy; Kidney Diseases - pathology; Kidney Diseases - physiopathology; Kidney Tubules, Proximal - pathology; Kidney Tubules, Proximal - physiology; Male; Mice; Mice, Inbred C57BL; Transfection; Up-Regulation - physiology; Von Hippel-Lindau Tumor Suppressor Protein - genetics; Von Hippel-Lindau Tumor Suppressor Protein - metabolism
• ISSN: 1931-857X
• DOI: 10.1152/ajprenal.90209.2008

Chronic hypoxia accelerates renal fibrosis. The chief mediator of the hypoxic response is hypoxia-inducible factor 1 (HIF-1) and its oxygen-sensitive component HIF-1alpha. HIF-1 regulates a wide variety of genes, some of which are closely associated with tissue fibrosis. To determine the specific role of HIF-1 in renal fibrosis, we generated a knockout mouse in which tubular epithelial expression of von Hippel-Lindau tumor suppressor (VHL), which acts as a ubiquitin ligase to promote proteolysis of HIF-1alpha, was targeted. We investigated the effect of VHL deletion (i.e., stable expression of HIF-1alpha) histologically and used the anti-HIF-1alpha agent [3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole] (YC-1) to test whether inhibition of HIF-1alpha could represent a novel approach to treating renal fibrosis. The area of renal fibrosis was significantly increased in a 5/6 renal ablation model of VHL-/- mice and in all VHL-/- mice at least 60 wk of age. Injection of YC-1 inhibited the progression of renal fibrosis in unilateral ureteral obstruction model mice. In conclusion, HIF-1alpha appears to be a critical contributor to the progression of renal fibrosis and could be a useful target for its treatment.