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Hypoxia-inducible factor-1? promotes glomerulosclerosis and regulates COL1A2 expression through interactions with Smad3.


ABSTRACT: The function of hypoxia-inducible factor-1? (HIF-1?) in chronic kidney disease is disputed. Here we report that interactions of HIF-1? with transforming growth factor-? (TGF-?) signaling may promote its fibrotic effects. Knockout of HIF-1? is protective against glomerulosclerosis and glomerular type-I collagen accumulation in a mouse podocyte ablation model. Transcriptional analysis of cultured renal cells showed that ?2(I) collagen expression is directly regulated by HIF-1? binding to a functional hypoxia-responsive element in its promoter at -335 relative to the transcription start site. Activation of COL1A2 transcription by HIF-1? occurred in the absence of hypoxia and is strongly enhanced by TGF-? signaling. TGF-?, in addition to increasing HIF-1? levels, increased both HIF-1? binding to the COL1A2 promoter and HIF-1? N-terminal transactivation domain activity. These effects of TGF-? on HIF-1? were inhibited in Smad3-null mouse embryonic fibroblasts, suggesting a requirement for Smad3. Phosphorylated Smad3 also associated with the -335 hypoxia-responsive element of the COL1A2 promoter independent of a Smad DNA binding sequence. Smad3 binding to the -335 hypoxia-responsive element required HIF-1? both in vitro and in kidney lysate from the disease model, suggesting formation of an HIF-1?-Smad3 transcriptional complex. Thus, HIF-1?-Smad3 has a novel interaction in glomerulosclerosis.

SUBMITTER: Baumann B 

PROVIDER: S-EPMC5026582 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Hypoxia-inducible factor-1α promotes glomerulosclerosis and regulates COL1A2 expression through interactions with Smad3.

Baumann Bethany B   Hayashida Tomoko T   Liang Xiaoyan X   Schnaper H William HW  

Kidney international 20160805 4


The function of hypoxia-inducible factor-1α (HIF-1α) in chronic kidney disease is disputed. Here we report that interactions of HIF-1α with transforming growth factor-β (TGF-β) signaling may promote its fibrotic effects. Knockout of HIF-1α is protective against glomerulosclerosis and glomerular type-I collagen accumulation in a mouse podocyte ablation model. Transcriptional analysis of cultured renal cells showed that α2(I) collagen expression is directly regulated by HIF-1α binding to a functio  ...[more]

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