Claudin 4 knockout mice: normal physiological phenotype with increased susceptibility to lung injury

Claudins are tight junction proteins that regulate paracellular ion permeability of epithelium and endothelium. Claudin 4 has been reported to function as a paracellular sodium barrier and is one of three major claudins expressed in lung alveolar epithelial cells (AEC). To directly assess the role o...

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Bibliographic Details
Published in:American journal of physiology. Lung cellular and molecular physiology 2014-10, Vol.307 (7), p.L524-L536
Main Authors: Kage, Hidenori, Flodby, Per, Gao, Danping, Kim, Yong Ho, Marconett, Crystal N, DeMaio, Lucas, Kim, Kwang-Jin, Crandall, Edward D, Borok, Zea
Format: Article
Language:English
Subjects:
Acute Lung Injury - genetics
Acute Lung Injury - physiopathology
Alveolar Epithelial Cells - physiology
Animals
Capillary Permeability
Cells
Cells, Cultured
Claudin-4 - genetics
Claudin-4 - metabolism
Female
Gene Knockout Techniques
Genetic Predisposition to Disease
Genotype & phenotype
Homeostasis
Hyperoxia - genetics
Hyperoxia - metabolism
Lung - pathology
Lung diseases
Mice
Mice, 129 Strain
Mice, Knockout
Phenotype
Rodents
Transcriptome
Ventilator-Induced Lung Injury - genetics
Ventilator-Induced Lung Injury - physiopathology
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Summary:Claudins are tight junction proteins that regulate paracellular ion permeability of epithelium and endothelium. Claudin 4 has been reported to function as a paracellular sodium barrier and is one of three major claudins expressed in lung alveolar epithelial cells (AEC). To directly assess the role of claudin 4 in regulation of alveolar epithelial barrier function and fluid homeostasis in vivo, we generated claudin 4 knockout (Cldn4 KO) mice. Unexpectedly, Cldn4 KO mice exhibited normal physiological phenotype although increased permeability to 5-carboxyfluorescein and decreased alveolar fluid clearance were noted. Cldn4 KO AEC monolayers exhibited unchanged ion permeability, higher solute permeability, and lower short-circuit current compared with monolayers from wild-type mice. Claudin 3 and 18 expression was similar between wild-type and Cldn4 KO alveolar epithelial type II cells. In response to either ventilator-induced lung injury or hyperoxia, claudin 4 expression was markedly upregulated in wild-type mice, whereas Cldn4 KO mice showed greater degrees of lung injury. RNA sequencing, in conjunction with differential expression and upstream analysis after ventilator-induced lung injury, suggested Egr1, Tnf, and Il1b as potential mediators of increased lung injury in Cldn4 KO mice. These results demonstrate that claudin 4 has little effect on normal lung physiology but may function to protect against acute lung injury.
ISSN:1040-0605
1522-1504
DOI:10.1152/ajplung.00077.2014