Interdependence of HIF-1α and TGF-β3/Smad3 signaling in normoxic and hypoxic renal epithelial cell collagen expression

Rajit K. Basu, Susan Hubchak, Tomoko Hayashida, Constance E. Runyan, Paul T. Schumacker, H. William Schnaper

Research output: Contribution to journalArticlepeer-review

84 Scopus citations

Abstract

Increasing evidence suggests that chronic kidney disease may develop following acute kidney injury and that this may be due, in part, to hypoxia-related phenomena. Hypoxia-inducible factor (HIF) is stabilized in hypoxic conditions and regulates multiple signaling pathways that could contribute to renal fibrosis. As transforming growth factor (TGF)-(3 is known to mediate renal fibrosis, we proposed a profibrotic role for cross talk between the TGF-(31 and HIF-1a signaling pathways in kidney cells. Hypoxic incubation increased HIF-1a protein expression in cultured human renal tubular epithelial cells and mouse embryonic fibroblasts. TGF-(31 treatment further increased HIF-1a expression in cells treated with hypoxia and also increased HIF-1a in normoxic conditions. TGF-(31 did not increase HIF-1a mRNA levels nor decrease the rate of protein degradation, suggesting that it enhances normoxic HIF-1a translation. TGF-(3 receptor (ALK5) kinase activity was required for increased HIF-1a expression in response to TGF-(31, but not to hypoxia. A dominant negative Smad3 decreased the TGF-(3-stimulated reporter activity of a HIF-1a-sensitive hypoxia response element. Conversely, a dominant negative HIF-1a construct decreased Smad-binding element promoter activity in response to TGF-(3. Finally, blocking HIF-1a transcription with a biochemical inhibitor, a dominant negative construct, or gene-specific knockdown decreased basal and TGF-(31-stimulated type I collagen expression, while HIF-1a overexpres-sion increased both. Taken together, our data demonstrate cooperation in signaling between Smad3 and HIF-1a and suggest a new paradigm in which HIF-1a is necessary for normoxic, TGF-(31-stimulated renal cell fibrogenesis.

Original languageEnglish (US)
Pages (from-to)898-905
Number of pages8
JournalAmerican Journal of Physiology - Renal Physiology
Volume300
Issue number4
DOIs
StatePublished - Apr 1 2011

Keywords

  • Acute kidney injury
  • Fibrosis

ASJC Scopus subject areas

  • Physiology
  • Urology

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