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Pflügers Archiv - European Journal of Physiology

, Volume 470, Issue 11, pp 1615–1631 | Cite as

Loss of barrier integrity in alveolar epithelial cells downregulates ENaC expression and activity via Ca2+ and TRPV4 activation

  • André Dagenais
  • Julie Desjardins
  • Waheed Shabbir
  • Antoine Roy
  • Dominic Filion
  • Rémy Sauvé
  • Yves Berthiaume
Molecular and cellular mechanisms of disease
Part of the following topical collections:
  1. Molecular and cellular mechanisms of disease

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.

Keywords

Epithelial Na channel ENaC TRPV4 Ca2+ wave Mechanotransduction Alveolar epithelial cells Lung injury Loss of barrier integrity 

Notes

Acknowledgements

This work is dedicated to the memory of Gregory Voisin who participated to the identification of TRPV channels in alveolar epithelial cells.

Funding information

This work was funded by the IRCM Gosselin-Lamarre chair in clinical research.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

424_2018_2182_MOESM1_ESM.docx (13 kb)
ESM 1 (DOCX 13 kb)
424_2018_2182_MOESM2_ESM.pdf (199 kb)
ESM 2 Detection of TRPV4 channel activity by patch clamp in alveolar epithelial cells (PDF 198 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Institut de recherches cliniques de MontréalQuebecCanada
  2. 2.Département de médecineUniversité de MontréalMontrealCanada
  3. 3.Institute of Pharmacology and ToxicologyUniversity of ViennaViennaAustria
  4. 4.Département de pharmacologie et physiologieUniversité de MontréalMontrealCanada

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