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Am J Physiol Renal Physiol. 2008 Oct;295(4):F1023-9. doi: 10.1152/ajprenal.90209.2008. Epub 2008 Jul 30.

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

Author information

1
First Department of Internal Medicine, Nara Medical University, 840 Shijo, Kashihara, Nara 634-8522, Japan.

Abstract

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.

PMID:
18667485
PMCID:
PMC4250235
DOI:
10.1152/ajprenal.90209.2008
[Indexed for MEDLINE]
Free PMC Article

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