Impact of KvLQT1 potassium channel modulation on alveolar fluid homeostasis in an animal model of thiourea-induced lung edema

Mélissa Aubin Vega; Alban Girault; Damien Adam; Jasmine Chebli; Anik Privé; Émilie Maillé; Annette Robichaud; Emmanuelle Brochiero

doi:10.3389/fphys.2022.1069466

Impact of KvLQT1 potassium channel modulation on alveolar fluid homeostasis in an animal model of thiourea-induced lung edema

Front Physiol. 2023 Jan 9:13:1069466. doi: 10.3389/fphys.2022.1069466. eCollection 2022.

Authors

Mélissa Aubin Vega^{1

2}, Alban Girault^{1

2

3}, Damien Adam^{1

2}, Jasmine Chebli^{1

2}, Anik Privé¹, Émilie Maillé¹, Annette Robichaud⁴, Emmanuelle Brochiero^{1

2}

Affiliations

¹ Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada.
² Département de Médecine, Université de Montréal, Montréal, QC, Canada.
³ Laboratoire de Physiologie Cellulaire et Moléculaire (LPCM), Amiens, France.
⁴ SCIREQ Scientific Respiratory Equipment Inc., Montréal, QC, Canada.

Abstract

Alveolar ion and fluid absorption is essential for lung homeostasis in healthy conditions as well as for the resorption of lung edema, a key feature of acute respiratory distress syndrome. Liquid absorption is driven by active transepithelial sodium transport, through apical ENaC Na⁺ channels and basolateral Na⁺/K⁺-ATPase. Our previous work unveiled that KvLQT1 K⁺ channels also participate in the control of Na⁺/liquid absorption in alveolar epithelial cells. Our aim was to further investigate the function of KvLQT1 channels and their interplay with other channels/transporters involved in ion/liquid transport in vivo using adult wild-type (WT) and KvLQT1 knock-out (KO) mice under physiological conditions and after thiourea-induced lung edema. A slight but significant increase in water lung content (WLC) was observed in naïve KvLQT1-KO mice, relative to WT littermates, whereas lung function was generally preserved and histological structure unaltered. Following thiourea-induced lung edema, KvLQT1-KO did not worsen WLC or lung function. Similarly, lung edema was not aggravated by the administration of a KvLQT1 inhibitor (chromanol). However, KvLQT1 activation (R-L3) significantly reduced WLC in thiourea-challenged WT mice. The benefits of R-L3 were prevented in KO or chromanol-treated WT mice. Furthermore, R-L3 treatment had no effect on thiourea-induced endothelial barrier alteration but restored or enhanced the levels of epithelial alveolar AQP5, Na⁺/K⁺-ATPase, and ENaC expressions. Altogether, the results indicate the benefits of KvLQT1 activation in the resolution of lung edema, probably through the observed up-regulation of epithelial alveolar channels/transporters involved in ion/water transport.

Keywords: AQP5; ENaC; Na+/K+-ATPase; animal model; ion/liquid transport; lung homeostasis; potassium channels; pulmonary edema.

Grants and funding

This work was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC, discovery grant RGPIN-2016-04378 to EB), the Canadian Institutes of Health Research (CIHR grants MOP-111054, PJT153406 and PJT166004 to EB), CRCHUM and Université de Montréal (scholarship to EB). MAV, AG, DA, and JC also acknowledge studentships from the NSERC (MAV), the Fonds de Recherche du Québec-Santé (FRQ-S, MAV, AG, DA, JC), the Respiratory Health Research Network of Quebec (AG). The CRCHUM is supported by a Centre grant from FRQ-S. The funders have no role in study design, data collection, and interpretation, or the decision to submit the work for publication.