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 promotes proteolysis of HIF-1 as a ubiquitin ligase, was targeted. We investigated the effect of VHL deletion (i.e. stable expression of HIF-1) histologically and used the anti-HIF-1 agent YC-1 (3-(5'- hydroxymethyl-2'-furyl)-1-benzyl indazole) 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 weeks 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.