Transient receptor potential vanilloid 4 (TRPV4) channels are essential for alveolar epithelial cell function

Abstract

Ischemia‐reperfusion‐induced edema formation as one of the most common and significant causes of morbidity and mortality after lung transplantation can be mimicked ex‐vivo in isolated perfused mouse lungs (IPL). Transient receptor potential vanilloid 4 (TRPV4) is a non‐selective cation channel expressed in lung endothelium where increased channel activity has been shown to compromise endothelial barrier function. Here we show enhanced edema formation in TRPV4‐deficient (TRPV4−/−) IPL compared to wild‐type (WT) controls in response to ischemia and reperfusion, indicating a protective role of TRPV4 to maintain the alveolar epithelial barrier. By immunohistochemistry or mRNA profiling, we detected TRPV4 in bronchial epithelium, alveolar type I (ATI) and alveolar type II (ATII) cells. Genetic ablation of TRPV4 resulted in reduced expression and plasma membrane insertion of the water conducting aquaporin‐5 (AQP‐5) channel in ATI cells compared to WT mice. Analysis of isolated primary TRPV4‐deficient ATII cells revealed a reduced expression of surfactant protein C (SP‐C), which is essential for decreasing surface tension and alveolar fluid homeostasis. The TRPV4 activator GSK1016790A induced increases in current densities only in WT but not in TRPV4−/− ATII cells. Although the ability of TRPV4−/− ATII cells to differentiate to ATI cells was unchanged, epithelial mesenchymal transition (EMT) of TRPV4−/− ATII cells was impaired and migration and cell barrier function of TRPV4−/− ATI cells was reduced. Moreover, TRPV4−/− lungs of adult mice developed significantly larger mean chord lengths and altered lung function compared to WT lungs. Therefore, our data highlight novel essential functions of TRPV4 channels in alveolar epithelial cells and in the protection from edema formation. Support or Funding Information This study was funded by the Deutsche Forschungsgemeinschaft (TRR 152 (AD, GKC, CG), GRK 2338 (AD, CG)) and the German Center for Lung Research (DZL) (AD, MB, NW, TG). Phenotypes in alveolar epithelial cells after ablation of TRPV4. See text for details.