Lung disease phenotypes caused by overexpression of combinations of α-, β-, and γ-subunits of the epithelial sodium channel in mouse airways

Am J Physiol Lung Cell Mol Physiol. 2018 Feb 1;314(2):L318-L331. doi: 10.1152/ajplung.00382.2017. Epub 2017 Oct 26.


The epithelial Na+ channel (ENaC) regulates airway surface hydration. In mouse airways, ENaC is composed of three subunits, α, β, and γ, which are differentially expressed (α > β > γ). Airway-targeted overexpression of the β subunit results in Na+ hyperabsorption, causing airway surface dehydration, hyperconcentrated mucus with delayed clearance, lung inflammation, and perinatal mortality. Notably, mice overexpressing the α- or γ-subunit do not exhibit airway Na+ hyperabsorption or lung pathology. To test whether overexpression of multiple ENaC subunits produced Na+ transport and disease severity exceeding that of βENaC-Tg mice, we generated double (αβ, αγ, βγ) and triple (αβγ) transgenic mice and characterized their lung phenotypes. Double αγENaC-Tg mice were indistinguishable from WT littermates. In contrast, double βγENaC-Tg mice exhibited airway Na+ absorption greater than that of βENaC-Tg mice, which was paralleled by worse survival, decreased mucociliary clearance, and more severe lung pathology. Double αβENaC-Tg mice exhibited Na+ transport rates comparable to those of βENaC-Tg littermates. However, αβENaC-Tg mice had poorer survival and developed severe parenchymal consolidation. In situ hybridization (RNAscope) analysis revealed both alveolar and airway αENaC-Tg overexpression. Triple αβγENaC-Tg mice were born in Mendelian proportions but died within the first day of life, and the small sample size prevented analyses of cause(s) of death. Cumulatively, these results indicate that overexpression of βENaC is rate limiting for generation of pathological airway surface dehydration. Notably, airway co-overexpression of β- and γENaC had additive effects on Na+ transport and disease severity, suggesting dose dependency of these two variables.

Keywords: CCSP-driven overexpression; epithelial sodium transport; mucociliary clearance; mucus concentration; α-, β-, γ-ENaC subunits.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Epithelial Sodium Channels / genetics
  • Epithelial Sodium Channels / metabolism*
  • Lung Diseases / etiology
  • Lung Diseases / metabolism
  • Lung Diseases / pathology*
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Phenotype
  • Pneumonia / etiology
  • Pneumonia / metabolism
  • Pneumonia / pathology*
  • Respiratory Mucosa / metabolism
  • Respiratory Mucosa / pathology*
  • Signal Transduction


  • Epithelial Sodium Channels
  • Scnn1b protein, mouse
  • Scnn1g protein, mouse