title: HIF-1α mediates Hypoxia-induced epithelial-mesenchymal transition in peritoneal mesothelial cells.
abstract: The epithelial-to-mesenchymal transition (EMT) of peritoneal mesothelial cells plays a pivotal role in the development of peritoneal fibrosis. The pathological effects of hypoxia on mesothelial cell EMT have not been fully elucidated. In this study, we, therefore, investigated the effects of hypoxia on EMT in mesothelial cells. Human mesothelial (MeT-5A) cells and primary-cultured rat mesothelial cells were cultured under hypoxic conditions (1% O(2)) for up to 72 h. Changes in cell type were then determined by investigating changes in morphology and in expression of epithelial (E-cadherin and occludin) and mesenchymal (fibronectin-1, vimentin and α-smooth muscle actin) cell markers. In some cases, MeT-5A cells were cultured under hypoxic conditions with a HIF-1α inhibitor and then assessed for changes in morphology and for altered expression of signaling molecules, such as HIF-1α, Snail-1, vascular endothelial growth factor (VEGF), and matrix metalloproteinase-2 (MMP-2). Levels of HIF-1α, Snail-1, VEGF, and MMP-2 in Met-5A cells were increased by hypoxia. Levels of epithelial cell markers were decreased and those of mesenchymal cell markers were increased. Cell morphology also changed from a cobblestone-like monolayer to spindle-shaped fibroblast-like cells in response to hypoxia. Inhibition of HIF-1α signaling by a HIF-1α inhibitor abrogated these changes. The cell marker and morphological changes induced by hypoxia were also observed in primary-cultured rat mesothelial cells. We can conclude that hypoxia induces EMT in mesothelial cells by activating HIF-1α. This finding indicates that hypoxia has pivotal roles in the development of peritoneal fibrosis in peritoneal dialysis patients.
authors.affiliation: a Division of Nephrology, Department of Integrated Medicine , Saitama Medical Center, Jichi Medical University , Saitama , Japan ;
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Morishita
authors.affiliation: a Division of Nephrology, Department of Integrated Medicine , Saitama Medical Center, Jichi Medical University , Saitama , Japan ;
authors.forename: Susumu
authors.initials: S
authors.lastname: Ookawara
authors.affiliation: a Division of Nephrology, Department of Integrated Medicine , Saitama Medical Center, Jichi Medical University , Saitama , Japan ;
authors.forename: Ichiro
authors.initials: I
authors.lastname: Hirahara
authors.affiliation: b Division of Nephrology, Department of Internal Medicine , Jichi Medical University , Tochigi , Japan.
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Muto
authors.affiliation: b Division of Nephrology, Department of Internal Medicine , Jichi Medical University , Tochigi , Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nagata
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000502:physiology*; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D008297:Male; D010537:Peritoneum / Q000166:cytology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit
keywords: HIF-1α; Hypoxia; epithelial–mesenchymal transition; peritoneal mesothelial cells