Open AccessDeletion of the ubiquitin ligase Nedd4L in lung epithelia causes cystic fibrosis-like disease
Author(s) -
Toshihiro Kimura,
Hiroshi Kawabe,
Chunhe Jiang,
Wenbo Zhang,
Xiang Yun,
Lu Chen,
Michael W. Salter,
Nils Brose,
WeiYang Lu,
Daniela Rotin
Publication year - 2011
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.1010334108
Subject(s) - epithelial sodium channel , cystic fibrosis , cystic fibrosis transmembrane conductance regulator , ubiquitin ligase , lung , amiloride , fibrosis , idiopathic pulmonary fibrosis , knockout mouse , ubiquitin , bleomycin , biology , pathology , endocrinology , medicine , chemistry , biochemistry , receptor , organic chemistry , chemotherapy , gene , sodium
Cystic fibrosis is caused by impaired ion transport due to mutated cystic fibrosis transmembrane conductance regulator, accompanied by elevated activity of the amiloride-sensitive epithelial Na(+) channel (ENaC). Here we show that knockout of the ubiquitin ligase Nedd4L (Nedd4-2) specifically in lung epithelia (surfactant protein C-expressing type II and Clara cells) causes cystic fibrosis-like lung disease, with airway mucus obstruction, goblet cell hyperplasia, massive inflammation, fibrosis, and death by three weeks of age. These effects of Nedd4L loss are likely caused by enhanced ENaC function, as reflected by increased ENaC protein levels, increased lung dryness at birth, amiloride-sensitive dehydration of lung explants, and elevated ENaC currents in primary alveolar type II cells analyzed by patch clamp recordings. Moreover, the lung defects were rescued with administration of amiloride into the lungs of young knockout pups via nasal instillation. Our results therefore suggest that the ubiquitin ligase Nedd4L can suppress the onset of cystic fibrosis symptoms by inhibiting ENaC in lung epithelia.