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

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