title: Effects of dexamethasone on the TGF-β1-induced epithelial-to-mesenchymal transition in human peritoneal mesothelial cells.
abstract: The epithelial-to-mesenchymal transition (EMT) is known to have a role in appropriate embryonic development, the physiological response to injury and pathological events such as organ fibrosis and cancer progression. Glucocorticoid (GC), one of the most commonly used anti-inflammatory drugs, inhibits the deposition of extracellular matrix independent of its anti-inflammatory effect. The EMT of human peritoneal mesothelial cells (HPMCs) is a key mechanism of peritoneal fibrosis; however, it has not yet been investigated whether GC imposes any effect on the EMT of HPMCs. To investigate the therapeutic potential of GC on preserving peritoneal membrane function, we studied the effect of dexamethasone (DEXA), a synthetic GC, on the transforming growth factor-β1 (TGF-β1)-induced EMT in HPMCs. As assessed by changes in cell morphology, the expression of epithelial and mesenchymal cell markers (such as E-cadherin, ZO-1 and α-SMA, α-smooth muscle actin) and cell migration, DEXA inhibited the TGF-β1-induced EMT. RU486, a glucocorticoid receptor (GR) antagonist, blocked the effect of DEXA on the TGF-β1-induced EMT. Importantly, DEXA also induced the mesenchymal-to-epithelial transition of TGF-β1-stimulated HPMCs. The beneficial effect of DEXA on the TGF-β1-induced EMT was mediated through the amelioration of ERK and p38 mitogen-activated protein kinase (MAPK) phosphorylation; however, this effect was not related to the TGF-β1-induced activation of Smad2/3 signaling. DEXA inhibited glycogen synthase kinase-3β (GSK-3β) phosphorylation and the Snail upregulation induced by TGF-β1, which were also ameliorated by inhibitors of MAPK. In conclusion, this is the first study demonstrating the protective effect of DEXA on the EMT in TGF-β1-stimulated HPMCs by inhibiting MAPK activation, GSK-3β phosphorylation and Snail upregulation.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Ewha Medical Research Center, Ewha Womans University School of Medicine, Seoul, Korea.
authors.forename: Yang-Hee
authors.initials: YH
authors.lastname: Jang
authors.forename: Hyun-Soo
authors.initials: HS
authors.lastname: Shin
authors.forename: Hack
authors.initials: H
authors.lastname: Sun Choi
authors.forename: Eun-Sun
authors.initials: ES
authors.lastname: Ryu
authors.forename: Mi
authors.initials: M
authors.lastname: Jin Kim
authors.forename: Seog
authors.initials: S
authors.lastname: Ki Min
authors.forename: Joo-Ho
authors.initials: JH
authors.lastname: Lee
authors.forename: Hyeon
authors.initials: H
authors.lastname: Kook Lee
authors.forename: Kwang-Ho
authors.initials: KH
authors.lastname: Kim
authors.forename: Duk-Hee
authors.initials: DH
authors.lastname: Kang
mesh_terms: D000199:Actins / Q000378:metabolism; D000704:Analysis of Variance; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D004847:Epithelial Cells / Q000502:physiology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects* / Q000502:physiology; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D015735:Mifepristone; D056627:Peritoneal Fibrosis / Q000517:prevention & control*; D010537:Peritoneum / Q000166:cytology*; D010766:Phosphorylation / Q000187:drug effects; D060888:Real-Time Polymerase Chain Reaction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D062826:Zonula Occludens-1 Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D015415:Biomarkers; D015820:Cadherins; D000071250:Snail Family Transcription Factors; C569042:TJP1 protein, human; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D062826:Zonula Occludens-1 Protein; D015735:Mifepristone; D003907:Dexamethasone; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D048051:p38 Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3