Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition

J Clin Invest. 2007 Dec;117(12):3810-20. doi: 10.1172/JCI30487.

Abstract

Hypoxia has been proposed as an important microenvironmental factor in the development of tissue fibrosis; however, the underlying mechanisms are not well defined. To examine the role of hypoxia-inducible factor-1 (HIF-1), a key mediator of cellular adaptation to hypoxia, in the development of fibrosis in mice, we inactivated Hif-1alpha in primary renal epithelial cells and in proximal tubules of kidneys subjected to unilateral ureteral obstruction (UUO) using Cre-loxP-mediated gene targeting. We found that Hif-1alpha enhanced epithelial-to-mesenchymal transition (EMT) in vitro and induced epithelial cell migration through upregulation of lysyl oxidase genes. Genetic ablation of epithelial Hif-1alpha inhibited the development of tubulointerstitial fibrosis in UUO kidneys, which was associated with decreased interstitial collagen deposition, decreased inflammatory cell infiltration, and a reduction in the number of fibroblast-specific protein-1-expressing (FSP-1-expressing) interstitial cells. Furthermore, we demonstrate that increased renal HIF-1alpha expression is associated with tubulointerstitial injury in patients with chronic kidney disease. Thus, we provide clinical and genetic evidence that activation of HIF-1 signaling in renal epithelial cells is associated with the development of chronic renal disease and may promote fibrogenesis by increasing expression of extracellular matrix-modifying factors and lysyl oxidase genes and by facilitating EMT.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium-Binding Proteins / biosynthesis
  • Calcium-Binding Proteins / genetics
  • Cell Hypoxia
  • Cell Movement* / genetics
  • Chronic Disease
  • Collagen / biosynthesis
  • Collagen / genetics
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology
  • Extracellular Matrix / genetics
  • Extracellular Matrix / metabolism
  • Extracellular Matrix / pathology
  • Fibrosis
  • Hypoxia / genetics
  • Hypoxia / metabolism*
  • Hypoxia / pathology
  • Hypoxia-Inducible Factor 1, alpha Subunit / biosynthesis*
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Kidney Tubules, Proximal / metabolism*
  • Kidney Tubules, Proximal / pathology
  • Mice
  • Mice, Knockout
  • Protein-Lysine 6-Oxidase / biosynthesis
  • Protein-Lysine 6-Oxidase / genetics
  • S100 Calcium-Binding Protein A4
  • S100 Proteins
  • Signal Transduction / genetics
  • Up-Regulation / genetics
  • Ureteral Obstruction / genetics
  • Ureteral Obstruction / metabolism*
  • Ureteral Obstruction / pathology

Substances

  • Calcium-Binding Proteins
  • FSP1 protein, human
  • HIF1A protein, human
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • S100 Calcium-Binding Protein A4
  • S100 Proteins
  • S100a4 protein, mouse
  • Collagen
  • Protein-Lysine 6-Oxidase