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

Kuniko Kimura, Masayuki Iwano*, Debra F. Higgins, Yukinari Yamaguchi, Kimihiko Nakatani, Koji Harada, Atsushi Kubo, Yasuhiro Akai, Erinn B. Rankin, Eric G. Neilson, Volker H. Haase, Yoshihiko Saito

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

228 Scopus citations

Abstract

Chronic hypoxia accelerates renal fibrosis. The chief mediator of the hypoxic response is hypoxiainducible factor 1 (HIF-1) and its oxygen-sensitive component HIF-1α. 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-1α, was targeted. We investigated the effect of VHL deletion (i.e., stable expression of HIF-1α) histologically and used the anti-HIF-1α agent [3-(5′-hydroxymethyl-2′-furyl)-1-benzyl indazole] (YC-1) to test whether inhibition of HIF-1α 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-1α appears to be a critical contributor to the progression of renal fibrosis and could be a useful target for its treatment.

Original languageEnglish (US)
Pages (from-to)F1023-F1029
JournalAmerican Journal of Physiology - Renal Physiology
Volume295
Issue number4
DOIs
StatePublished - Oct 2008

Keywords

  • Fibroblast-specific protein 1
  • Fibrosis
  • HIF-1
  • Hypoxia
  • VHL

ASJC Scopus subject areas

  • Urology
  • Physiology

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