Stable expression of HIF-1alpha 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-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.
Kimura
Kuniko
K
First Department of Internal Medicine, Nara Medical University, 840 Shijo, Kashihara, Nara 634-8522, Japan.
Iwano
Masayuki
M
Higgins
Debra F
DF
Yamaguchi
Yukinari
Y
Nakatani
Kimihiko
K
Harada
Koji
K
Kubo
Atsushi
A
Akai
Yasuhiro
Y
Rankin
Erinn B
EB
Neilson
Eric G
EG
Haase
Volker H
VH
Saito
Yoshihiko
Y
D000375:Aging / Q000473:pathology / Q000502:physiology; D000818:Animals; D004195:Disease Models, Animal; D020536:Enzyme Activators / Q000494:pharmacology; D004847:Epithelial Cells / Q000473:pathology / Q000502:physiology*; D005260:Female; D005355:Fibrosis; D017353:Gene Deletion; D015870:Gene Expression / Q000502:physiology; D000860:Hypoxia / Q000473:pathology / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D007191:Indazoles / Q000494:pharmacology; D007674:Kidney Diseases / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D007687:Kidney Tubules, Proximal / Q000473:pathology / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D014162:Transfection; D015854:Up-Regulation / Q000502:physiology; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism
D020536:Enzyme Activators; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007191:Indazoles; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C494469:VHL protein, mouse