Proliferative regulation of alveolar epithelial type 2 progenitor cells by human Scnn1d gene.

Theranostics 2019

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Lung epithelial sodium channel (ENaC) encoded by Scnn1 genes is essential for maintaining transepithelial salt and fluid homeostasis in the airway and the lung. Compared to α, β, and γ subunits, the role of respiratory δ-ENaC has not been studied in vivo due to the lack of animal models. Methods: We characterized full-length human δ802-ENaC expressed in both Xenopus oocytes and humanized transgenic mice. AT2 proliferation and differentiation in 3D organoids were analysed with FACS and a confocal microscope. Both two-electrode voltage clamp and Ussing chamber systems were applied to digitize δ802-ENaC channel activity. Immunoblotting was utilized to analyse δ802-ENaC protein. Transcripts of individual ENaC subunits in human lung tissues were quantitated with qPCR. Results: The results indicate that δ802-ENaC functions as an amiloride-inhibitable Na+ channel. Inhibitory peptide α-13 distinguishes δ802- from α-type ENaC channels. Modified proteolysis of γ-ENaC by plasmin and aprotinin did not alter the inhibition of amiloride and α-13 peptide. Expression of δ802-ENaC at the apical membrane of respiratory epithelium was detected with biophysical features similar to those of heterologously expressed channels in oocytes. δ802-ENaC regulated alveologenesis through facilitating the proliferation of alveolar type 2 epithelial cells. Conclusion: The humanized mouse line conditionally expressing human δ802-ENaC is a novel model for studying the expression and function of this protein in vivo . © The author(s).

Citation

Runzhen Zhao, Gibran Ali, Jianjun Chang, Satoshi Komatsu, Yoshikazu Tsukasaki, Hong-Guang Nie, Yongchang Chang, Mo Zhang, Yang Liu, Krishan Jain, Bock-Gie Jung, Buka Samten, Dianhua Jiang, Jiurong Liang, Mitsuo Ikebe, Michael A Matthay, Hong-Long Ji. Proliferative regulation of alveolar epithelial type 2 progenitor cells by human Scnn1d gene. Theranostics. 2019;9(26):8155-8170