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

Abstract

Competing interests:The authors declare that no competing interests exist. ischemia and reperfusion, indicating a protective role of TRPV4 to maintain the alveolar epithelial barrier. TRPV4 was detected in bronchial epithelium, alveolar type I (ATI) and alveolar type II (ATII) cells by immunohistochemistry or mRNA profiling. Genetic ablation of TRPV4 resulted in reduced expression and plasma membrane insertion of water conducting aquaporin-5 (AQP-5) channels in ATI cells compared to WT mice.Analysis of isolated primary TRPV4-/-ATII cells revealed a reduced expression of pro surfactant protein-C (pSP-C) a precursor of a protein important for decreasing surface tension and for alveolar fluid homeostasis. Moreover, the TRPV4 activator GSK1016790A induced increases in current densities only in WT but not in TRPV4-/-ATII cells. On a molecular level ablation of TRPV4 induced less Ca 2+ -mediated nuclear translocation of nuclear factor of activated T-cells (NFAT) to the nucleus, which may be responsible for reduced expression of the identified proteins. Although the ability of TRPV4-/-ATII to differentiate to ATI cells was unchanged, migration of TRPV4deficient ATI cells was reduced and cell barrier function was impaired. Moreover, TRPV4-/-lungs of adult mice developed significantly larger mean chord lengths and altered lung function compared to WT lungs. The findings of Weber et al. highlights novel essential functions of TRPV4 channels in alveolar epithelial cells and in the protection from edema formation. Akazawa Y, Yuki T, Yoshida H, Sugiyama Y, Inoue, S. 2013. Activation of TRPV4 strengthens the tight-junction barrier in human epidermal keratinocytes. Skin Pharmacol Physiol 26: 15-21. Alpizar YA, Boonen B, Sanchez A, Jung C, Lopez-Requena A, Naert R, Steelant B, Luyts K, Plata C, De Vooght V et al. 2017. TRPV4 activation triggers protective responses to bacterial lipopolysaccharides in airway epithelial cells. Nature communications 8: 1059. Alvarez DF, King JA, Weber D, Addison E, Liedtke W, Townsley MI 2006. Transient receptor potential vanilloid 4-mediated disruption of the alveolar septal barrier: a novel mechanism of acute lung injury. Circ Res 99: 988-995. Balakrishna S, Song W, Achanta S, Doran SF, Liu B, Kaelberer MM, Yu Z, Sui A, Cheung M, Leishman E et al. 2014. TRPV4 inhibition counteracts edema and inflammation and improves pulmonary function and oxygen saturation in chemically induced acute lung injury. American journal of physiology Lung cellular and molecular physiology 307: L158-172. Corti M, Brody AR, and Harrison JH 1996. Isolation and primary culture of murine alveolar type II cells. American journal of respiratory cell and molecular biology 14: 309-315. Curcic S, Schober R, Schindl R, Groschner K 2019. TRPC-mediated Ca(2+) signaling and control of cellular functions. Semin Cell Dev Biol. in press de Perrot M, Liu M, Waddell TK, and Keshavjee S 2003. Ischemia-reperfusion-induced lung injury. American journal of respiratory and critical care medicine 167: 490-511. Desai TJ, Brownfield DG, Krasnow ...