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Chicago Ridge, IL, United States

Basu R.K.,Divisions of Critical Care | Basu R.K.,Childrens Memorial Research Center | Hubchak S.,Divisions of Kidney Diseases | Hayashida T.,Divisions of Kidney Diseases | And 6 more authors.
American Journal of Physiology - Renal Physiology | Year: 2011

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.© 2011 by the American Physiological Society.

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