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

¹First Department of Internal Medicine, Nara Medical University, Nara, Japan; ²Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, Pennsylvania; and ³Department of Medicine and Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee

Submitted 25 March 2008 ; accepted in final form 24 July 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-1. 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-1, was targeted. We investigated the effect of VHL deletion (i.e., stable expression of HIF-1) histologically and used the anti-HIF-1 agent [3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole] (YC-1) to test whether inhibition of HIF-1 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-1 appears to be a critical contributor to the progression of renal fibrosis and could be a useful target for its treatment.

hypoxia; HIF-1; VHL; fibrosis; fibroblast-specific protein 1

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