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Kidney Int. 2009 Jun;75(12):1278-1287. doi: 10.1038/ki.2009.62. Epub 2009 Mar 11.

Hypoxia-inducible factor-1alpha induces Twist expression in tubular epithelial cells subjected to hypoxia, leading to epithelial-to-mesenchymal transition.

Author information

1
Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
2
State Key Laboratory of Cancer Biology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China; Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
3
State Key Laboratory of Cancer Biology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
4
State Key Laboratory of Cancer Biology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China. Electronic address: fandaim@fmmu.edu.cn.

Abstract

Epithelial-to-mesenchymal transition (EMT) induced by chronic hypoxia is one of the critical causes of renal fibrosis. Twist, a basic helix-loop-helix transcription factor, is believed to be important in promoting EMT. We found that the expression of Twist was increased in human tubule cell lines (HK-2 and HKC) grown under hypoxic conditions. This was accompanied by reduced expression of the epithelial markers E-cadherin and ZO-1 and enhanced expression of the mesenchymal markers vimentin and alpha-smooth muscle actin. When Twist was overexpressed in these cells it induced a mesenchymal phenotype, whereas its knockdown by short interfering RNA (siRNA) effectively reversed hypoxia-induced EMT. We showed that transfection with siRNA to hypoxia-inducible factor-1alpha (HIF-1alpha), another basic helix-loop-helix transcription factor, reduced Twist expression. Twist promoters contain HIF1-alpha-binding sites and transfection of reporter constructs using the promoter showed increased transcription in cells subjected to hypoxia. Electrophoretic mobility shift and chromatin immunoprecipitation assays identified the presence of a functional HIF-1alpha-binding site within the proximal Twist gene promoter. In an in vivo assay using the rat remnant kidney we found that both Twist and HIF-1alpha were overexpressed in tubular epithelial cells showing EMT. These studies suggest that HIF-1alpha induces Twist expression in hypoxic tubular cells and that this plays a role in EMT during renal fibrogenesis.

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PMID:
19279556
DOI:
10.1038/ki.2009.62
[Indexed for MEDLINE]
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