title: Hypoxia-inducible factor-1α promotes glomerulosclerosis and regulates COL1A2 expression through interactions with Smad3.
abstract: 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.
authors: Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. Electronic address: bbaumann@u.northwestern.edu.
authors: Bethany
authors: B
authors: Baumann
authors: Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA; Division of Kidney Disease, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.
authors: Tomoko
authors: T
authors: Hayashida
authors: Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors: Xiaoyan
authors: X
authors: Liang
authors: Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA; Division of Kidney Disease, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.
authors: H William
authors: HW
authors: Schnaper
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism*; D004195:Disease Models, Animal; D005347:Fibroblasts; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D050199:Podocytes; D011401:Promoter Regions, Genetic; D051436:Renal Insufficiency, Chronic / Q000378:metabolism / Q000473:pathology*; D012598:Sclerosis; D015398:Signal Transduction; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: C000619309:Col1a2 protein, mouse; D024042:Collagen Type I; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D053773:Transforming Growth Factor beta1
keywords: TGF-β; fibrosis; glomerulus; hypoxia