title: Knockout mice reveal key roles for claudin 18 in alveolar barrier properties and fluid homeostasis.
abstract: Claudin proteins are major constituents of epithelial and endothelial tight junctions (TJs) that regulate paracellular permeability to ions and solutes. Claudin 18, a member of the large claudin family, is highly expressed in lung alveolar epithelium. To elucidate the role of claudin 18 in alveolar epithelial barrier function, we generated claudin 18 knockout (C18 KO) mice. C18 KO mice exhibited increased solute permeability and alveolar fluid clearance (AFC) compared with wild-type control mice. Increased AFC in C18 KO mice was associated with increased β-adrenergic receptor signaling together with activation of cystic fibrosis transmembrane conductance regulator, higher epithelial sodium channel, and Na-K-ATPase (Na pump) activity and increased Na-K-ATPase β1 subunit expression. Consistent with in vivo findings, C18 KO alveolar epithelial cell (AEC) monolayers exhibited lower transepithelial electrical resistance and increased solute and ion permeability with unchanged ion selectivity. Claudin 3 and claudin 4 expression was markedly increased in C18 KO mice, whereas claudin 5 expression was unchanged and occludin significantly decreased. Microarray analysis revealed changes in cytoskeleton-associated gene expression in C18 KO mice, consistent with observed F-actin cytoskeletal rearrangement in AEC monolayers. These findings demonstrate a crucial nonredundant role for claudin 18 in the regulation of alveolar epithelial TJ composition and permeability properties. Increased AFC in C18 KO mice identifies a role for claudin 18 in alveolar fluid homeostasis beyond its direct contributions to barrier properties that may, at least in part, compensate for increased permeability.
authors.affiliation: 1 Will Rogers Institute Pulmonary Research Center, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine.
authors.forename: Guanglei
authors.initials: G
authors.lastname: Li
authors.forename: Per
authors.initials: P
authors.lastname: Flodby
authors.forename: Jiao
authors.initials: J
authors.lastname: Luo
authors.forename: Hidenori
authors.initials: H
authors.lastname: Kage
authors.forename: Arnold
authors.initials: A
authors.lastname: Sipos
authors.forename: Danping
authors.initials: D
authors.lastname: Gao
authors.forename: Yanbin
authors.initials: Y
authors.lastname: Ji
authors.forename: LaMonta L
authors.initials: LL
authors.lastname: Beard
authors.forename: Crystal N
authors.initials: CN
authors.lastname: Marconett
authors.forename: Lucas
authors.initials: L
authors.lastname: DeMaio
authors.forename: Yong Ho
authors.initials: YH
authors.lastname: Kim
authors.forename: Kwang-Jin
authors.initials: KJ
authors.lastname: Kim
authors.forename: Ite A
authors.initials: IA
authors.lastname: Laird-Offringa
authors.forename: Parviz
authors.initials: P
authors.lastname: Minoo
authors.forename: Janice M
authors.initials: JM
authors.lastname: Liebler
authors.forename: Beiyun
authors.initials: B
authors.lastname: Zhou
authors.forename: Edward D
authors.initials: ED
authors.lastname: Crandall
authors.forename: Zea
authors.initials: Z
authors.lastname: Borok
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D062465:Claudin-3 / Q000378:metabolism; D062506:Claudin-4 / Q000378:metabolism; D062507:Claudin-5 / Q000378:metabolism; D057167:Claudins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D003599:Cytoskeleton / Q000378:metabolism; D004195:Disease Models, Animal; D017097:Electric Impedance; D004847:Epithelial Cells / Q000378:metabolism*; D005838:Genotype; D006706:Homeostasis; D006801:Humans; D017136:Ion Transport; D051379:Mice; D018345:Mice, Knockout; D062793:Occludin / Q000378:metabolism; D010539:Permeability; D010641:Phenotype; D011650:Pulmonary Alveoli / Q000378:metabolism* / Q000503:physiopathology; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D019108:Tight Junctions / Q000378:metabolism*; D055397:Ventilator-Induced Lung Injury / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology
chemical_list: C503552:Atp1b1 protein, mouse; D062465:Claudin-3; D062506:Claudin-4; D062507:Claudin-5; D057167:Claudins; C438899:Cldn18 protein, mouse; C568123:Cldn3 protein, mouse; C568158:Cldn4 protein, mouse; C491511:Cldn5 protein, mouse; D062793:Occludin; C568986:Ocln protein, mouse; D000254:Sodium-Potassium-Exchanging ATPase
keywords: alveolar fluid clearance; bioelectrical properties; permeability; tight junction; β2-adrenergic receptor