ENaC-mediated alveolar fluid clearance and lung fluid balance depend on the channel-activating protease 1.
Sodium transport via epithelial sodium channels (ENaC) expressed in alveolar epithelial cells (AEC) provides the driving force for removal of fluid from the alveolar space. The membrane-bound channel-activating protease 1 (CAP1/Prss8) activates ENaC in vitro in various expression systems. To study the role of CAP1/Prss8 in alveolar sodium transport and lung fluid balance in vivo, we generated mice lacking CAP1/Prss8 in the alveolar epithelium using conditional Cre-loxP-mediated recombination. Deficiency of CAP1/Prss8 in AEC induced in vitro a 40% decrease in ENaC-mediated sodium currents. Sodium-driven alveolar fluid clearance (AFC) was reduced in CAP1/Prss8-deficient mice, due to a 48% decrease in amiloride-sensitive clearance, and was less sensitive to beta(2)-agonist treatment. Intra-alveolar treatment with neutrophil elastase, a soluble serine protease activating ENaC at the cell surface, fully restored basal AFC and the stimulation by beta(2)-agonists. Finally, acute volume-overload increased alveolar lining fluid volume in CAP1/Prss8-deficient mice. This study reveals that CAP1 plays a crucial role in the regulation of ENaC-mediated alveolar sodium and water transport and in mouse lung fluid balance.
Planès
Carole
C
Département de Pharmacologie et de Toxicologie, Université de Lausanne, Lausanne, Switzerland.
Randrianarison
Nadia H
NH
Charles
Roch-Philippe
RP
Frateschi
Simona
S
Cluzeaud
Françoise
F
Vuagniaux
Grégoire
G
Soler
Paul
P
Clerici
Christine
C
Rossier
Bernard C
BC
Hummler
Edith
E
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism; D053503:Epithelial Sodium Channels / Q000235:genetics / Q000378:metabolism*; D015633:Extravascular Lung Water / Q000378:metabolism*; D017353:Gene Deletion; D015870:Gene Expression; D008168:Lung / Q000378:metabolism*; D051379:Mice; D011650:Pulmonary Alveoli / Q000166:cytology / Q000378:metabolism*; D011654:Pulmonary Edema / Q000378:metabolism; D020545:Respiratory Mucosa / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D014882:Water-Electrolyte Balance / Q000187:drug effects; D000099271:Prostasin
D000318:Adrenergic beta-Agonists; D053503:Epithelial Sodium Channels; D012697:Serine Endopeptidases; D000099271:Prostasin