Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition.
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.
Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Debra F
DF
Higgins
Kuniko
K
Kimura
Wanja M
WM
Bernhardt
Nikita
N
Shrimanker
Yasuhiro
Y
Akai
Bernd
B
Hohenstein
Yoshihiko
Y
Saito
Randall S
RS
Johnson
Matthias
M
Kretzler
Clemens D
CD
Cohen
Kai-Uwe
KU
Eckardt
Masayuki
M
Iwano
Volker H
VH
Haase
D000818:Animals; D002135:Calcium-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D015687:Cell Hypoxia; D002465:Cell Movement / Q000235:genetics; D002908:Chronic Disease; D003094:Collagen / Q000096:biosynthesis / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis* / Q000235:genetics; D007687:Kidney Tubules, Proximal / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008249:Protein-Lysine 6-Oxidase / Q000096:biosynthesis / Q000235:genetics; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; D015398:Signal Transduction / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics; D014517:Ureteral Obstruction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
D002135:Calcium-Binding Proteins; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C470944:S100a4 protein, mouse; C077591:S100A4 protein, human; D003094:Collagen; D008249:Protein-Lysine 6-Oxidase