title: FXYD1 negatively regulates Na(+)/K(+)-ATPase activity in lung alveolar epithelial cells.
abstract: Acute respiratory distress syndrome (ARDS) is clinical syndrome characterized by decreased lung fluid reabsorption, causing alveolar edema. Defective alveolar ion transport undertaken in part by the Na(+)/K(+)-ATPase underlies this compromised fluid balance, although the molecular mechanisms at play are not understood. We describe here increased expression of FXYD1, FXYD3 and FXYD5, three regulatory subunits of the Na(+)/K(+)-ATPase, in the lungs of ARDS patients. Transforming growth factor (TGF)-β, a pathogenic mediator of ARDS, drove increased FXYD1 expression in A549 human lung alveolar epithelial cells, suggesting that pathogenic TGF-β signaling altered Na(+)/K(+)-ATPase activity in affected lungs. Lentivirus-mediated delivery of FXYD1 and FXYD3 allowed for overexpression of both regulatory subunits in polarized H441 cell monolayers on an air/liquid interface. FXYD1 but not FXYD3 overexpression inhibited amphotericin B-sensitive equivalent short-circuit current in Ussing chamber studies. Thus, we speculate that FXYD1 overexpression in ARDS patient lungs may limit Na(+)/K(+)-ATPase activity, and contribute to edema persistence.
authors.affiliation: Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany; Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany; Department of Biochemistry, University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.
authors.forename: Łukasz A
authors.initials: ŁA
authors.lastname: Wujak
authors.affiliation: Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Blume
authors.affiliation: Department of Sports Medicine, Medical Clinic VII, University Hospital Heidelberg, University of Heidelberg, Translational Lung Research Center (TLRC), Member of the German Center for Lung Research (DZL), Heidelberg, Germany; Department of Medical Pharmacology, Acibadem University, İstanbul, Turkey.
authors.forename: Emel
authors.initials: E
authors.lastname: Baloğlu
authors.affiliation: Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany; Department of Biochemistry, University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Wygrecka
authors.affiliation: Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Jegor
authors.initials: J
authors.lastname: Wygowski
authors.affiliation: Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Herold
authors.affiliation: Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Mayer
authors.affiliation: Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.
authors.forename: István
authors.initials: I
authors.lastname: Vadász
authors.affiliation: Department of Pathology, Klinikum Frankfurt (Oder) GmbH, Frankfurt (Oder), Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Besuch
authors.affiliation: Department of Biochemistry, University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.
authors.forename: Heimo
authors.initials: H
authors.lastname: Mairbäurl
authors.affiliation: Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany; Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.affiliation: Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany; Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany. Electronic address: rory.morty@mpi-bn.mpg.de.
authors.forename: Rory E
authors.initials: RE
authors.lastname: Morty
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D007473:Ion Channels; D016086:Lentivirus / Q000235:genetics; D008168:Lung / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008840:Microfilament Proteins; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012128:Respiratory Distress Syndrome / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*
chemical_list: C091777:FXYD3 protein, human; C451410:FXYD5 protein, human; D007473:Ion Channels; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; D010750:Phosphoproteins; C069141:phospholemman; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase
keywords: ARDS; Edema; FXYD; Ion transport; Na(+)/K(+)-ATPase; TGF-β