Affordable Access

deepdyve-link
Publisher Website

Loss of β Epithelial Sodium Channel Function in Meibomian Glands Produces Pseudohypoaldosteronism 1-Like Ocular Disease in Mice.

Authors
  • Yu, Dongfang1
  • Saini, Yogesh2
  • Chen, Gang3
  • Ghio, Andrew J4
  • Dang, Hong3
  • Burns, Kimberlie A3
  • Wang, Yang3
  • Davis, Richard M5
  • Randell, Scott H3
  • Esther, Charles R Jr6
  • Paulsen, Friedrich7
  • Boucher, Richard C8
  • 1 Marsico Lung Institute/University of North Carolina Cystic Fibrosis Research Center, School of Medicine, Chapel Hill, North Carolina; Department of Pathology, Wake Forest School of Medicine, Winston-Salem, North Carolina.
  • 2 Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana.
  • 3 Marsico Lung Institute/University of North Carolina Cystic Fibrosis Research Center, School of Medicine, Chapel Hill, North Carolina.
  • 4 National Health and Environmental Effects Research Laboratory, Environmental Protection Agency, Chapel Hill, North Carolina.
  • 5 Department of Ophthalmology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
  • 6 Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
  • 7 Department of Anatomy II, Friedrich Alexander University Erlangen Nürnberg, Erlangen, Germany. , (Germany)
  • 8 Marsico Lung Institute/University of North Carolina Cystic Fibrosis Research Center, School of Medicine, Chapel Hill, North Carolina. Electronic address: [email protected]
Type
Published Article
Journal
American Journal Of Pathology
Publisher
Elsevier
Publication Date
Jan 01, 2018
Volume
188
Issue
1
Pages
95–110
Identifiers
DOI: 10.1016/j.ajpath.2017.09.016
PMID: 29107074
Source
Medline
License
Unknown

Abstract

Human subjects with pseudohypoaldosteronism-1 because of loss-of-function mutations in epithelial sodium channel (ENaC) subunits exhibit meibomian gland (MG) dysfunction. A conditional βENaC MG knockout (KO) mouse model was generated to elucidate the pathogenesis of absent ENaC function in the MG and associated ocular surface disease. βENaC MG KO mice exhibited a striking age-dependent, female-predominant MG dysfunction phenotype, with white toothpaste-like secretions observed obstructing MG orifices at 7 weeks of age. There were compensatory increases in tear production but higher tear sodium and indexes of mucin concentration in βENaC MG KO mice. Histologically, MG acinar atrophy was observed with ductal enlargement and ductal epithelial hyperstratification. Inflammatory cell infiltration was observed in both MG and conjunctiva of βENaC MG KO mice. In older βENaC MG KO mice (5 to 11 months), significant ocular surface pathologies were noted, including corneal opacification, ulceration, neovascularization, and ectasia. Inflammation in MG and conjunctiva was confirmed by increased cytokine gene and protein expression and positive Ly-6B.2 immunostaining. Cell proliferation assays revealed lower proliferation rates of MG cells derived from βENaC MG KO than control mice, suggesting that βENaC plays a role in cell renewal of mouse MG. Loss of βENaC function resulted in MG disease and severe ocular surface damage that phenocopied aspects of human pseudohypoaldosteronism-1 MG disease and was sex dependent.

Report this publication

Statistics

Seen <100 times