title: Salt-inducible kinase 1 is present in lung alveolar epithelial cells and regulates active sodium transport.
abstract: Salt-inducible kinase 1 (SIK1) in epithelial cells mediates the increases in active sodium transport (Na(+), K(+)-ATPase-mediated) in response to elevations in the intracellular concentration of sodium. In lung alveolar epithelial cells increases in active sodium transport in response to β-adrenergic stimulation increases pulmonary edema clearance. Therefore, we sought to determine whether SIK1 is present in lung epithelial cells and to examine whether isoproterenol-dependent stimulation of Na(+), K(+)-ATPase is mediated via SIK1 activity. All three SIK isoforms were present in airway epithelial cells, and in alveolar epithelial cells type 1 and type 2 from rat and mouse lungs, as well as from human and mouse cell lines representative of lung alveolar epithelium. In mouse lung epithelial cells, SIK1 associated with the Na(+), K(+)-ATPase α-subunit, and isoproterenol increased SIK1 activity. Isoproterenol increased Na(+), K(+)-ATPase activity and the incorporation of Na(+), K(+)-ATPase molecules at the plasma membrane. Furthermore, those effects were abolished in cells depleted of SIK1 using shRNA, or in cells overexpressing a SIK1 kinase-deficient mutant. These results provide evidence that SIK1 is present in lung epithelial cells and that its function is relevant for the action of isoproterenol during regulation of active sodium transport. As such, SIK1 may constitute an important target for drug discovery aimed at improving the clearance of pulmonary edema.
authors.affiliation: Membrane Signaling Networks, Atherosclerosis Research Unit, Department of Medicine, CMM, Karolinska Institutet, Karolinska University Hospital-Solna, Stockholm, Sweden.
authors.forename: Kristina
authors.initials: K
authors.lastname: Eneling
authors.forename: Jiwang
authors.initials: J
authors.lastname: Chen
authors.forename: Lynn C
authors.initials: LC
authors.lastname: Welch
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takemori
authors.forename: Jacob I
authors.initials: JI
authors.lastname: Sznajder
authors.forename: Alejandro M
authors.initials: AM
authors.lastname: Bertorello
mesh_terms: D000818:Animals; D001993:Bronchodilator Agents / Q000494:pharmacology; D002460:Cell Line; D006801:Humans; D017136:Ion Transport / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000201:enzymology*; D051381:Rats; D020545:Respiratory Mucosa / Q000187:drug effects / Q000201:enzymology*; D012964:Sodium / Q000378:metabolism*
chemical_list: D001993:Bronchodilator Agents; D012964:Sodium; D017346:Protein Serine-Threonine Kinases; C509080:SIK1 protein, human; C495376:Sik1 protein, mouse; C120299:Sik1 protein, rat; D007545:Isoproterenol