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- Title
Loss of barrier integrity in alveolar epithelial cells downregulates ENaC expression and activity via Ca<sup>2+</sup> and TRPV4 activation.
- Authors
Dagenais, André; Desjardins, Julie; Shabbir, Waheed; Roy, Antoine; Filion, Dominic; Sauvé, Rémy; Berthiaume, Yves
- Abstract
The epithelial Na channel (ENaC) plays an essential role in lung physiology by modulating the amount of liquid lining the respiratory epithelium. Here, we tested the effect of breaking alveolar epithelial cell barrier integrity on ENaC expression and function. We found that either mechanical wounding by scratching the monolayer or disruption of tight junction with EDTA induced a ~ 50% decrease of α,β and γENaC mRNA expression and an 80% reduction of ENaC short-circuit current (Isc) at 6 h. Scratching the cell monolayer generated a Ca2+ wave that spread from the margin of the scratch to distant cells. Pretreatment with BAPTA-AM, an intracellular Ca2+ chelator, abolished the effect of mechanical wounding and EDTA on αENaC mRNA expression, suggesting that [Ca2+]i is important for this modulation. We tested the hypothesis that a mechanosensitive channel such as TRPV4, a cationic channel known to increase [Ca2+]i, could mediate this effect. Activation of the channel with the TRPV4 specific agonist GSK-1016790A (GSK) decreased αENAC mRNA expression and almost completely abolished ENaC Isc. Pretreatment of alveolar epithelial cells with HC-067047 (HC0), a specific TRPV4 antagonist, reduced the extent of αENAC mRNA downregulation by mechanical wounding and EDTA. Altogether, our results suggest that mechanical stress induced by wounding or TRPV4-mediated loss of tight junction increases [Ca2+]i and elicits a Ca2+ wave that affects ENaC expression and function away from the site of injury. These data are important to better understand how Ca2+ signaling affects lung liquid clearance in injured lungs.
- Subjects
EPITHELIAL cells; SODIUM channels; CALCIUM channels; TRP channels; PROTEIN expression; LUNG physiology
- Publication
Pflügers Archiv: European Journal of Physiology, 2018, Vol 470, Issue 11, p1615
- ISSN
0031-6768
- Publication type
Article
- DOI
10.1007/s00424-018-2182-4