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

Bethany Baumann*, Tomoko Hayashida, Xiaoyan Liang, H. William Schnaper

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

57 Scopus citations


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 functional hypoxia-responsive element in its promoter at –335 relative to the transcription start site. Activation of COL1A2 transcription by HIF-1α occurred in the absence of hypoxia and is strongly enhanced by TGF-β signaling. TGF-β, in addition to increasing HIF-1α levels, increased both HIF-1α binding to the COL1A2 promoter and HIF-1α N-terminal transactivation domain activity. These effects of TGF-β on HIF-1α 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-1α both in vitro and in kidney lysate from the disease model, suggesting formation of an HIF-1α–Smad3 transcriptional complex. Thus, HIF-1α-Smad3 has a novel interaction in glomerulosclerosis.

Original languageEnglish (US)
Pages (from-to)797-808
Number of pages12
JournalKidney international
Issue number4
StatePublished - Oct 2016


  • TGF-β
  • fibrosis
  • glomerulus
  • hypoxia

ASJC Scopus subject areas

  • Nephrology


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