Role of Cation Channel TRPV4 in Mechanosensing, Myofibroblast Differentiation, and Pulmonary Fibrosis

• Published in: Annals of the American Thoracic Society Vol. 12; no. Supplement 1; pp. S74 - S75
• Main Authors: Rahaman, Shaik O., Grove, Lisa M., Southern, Brian D., Scheraga, Rachel G., Abraham, Susamma, Niese, Kathryn A., Ghosh, Sudakshina, Tschumperlin, Daniel J., Olman, Mitchell A.
• Format: Journal Article
• Language: English
• Published: New York American Thoracic Society 01.03.2015
• Subjects: Abstracts
• ISSN: 2329-6933; 2325-6621
• DOI: 10.1513/AnnalsATS.201411-531MG

Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disorder with marginally effective medical treatment. Myofibroblasts are critical to the fibrogenic lung repair process; however, the mechanism whereby the mechanical signal that leads to myofibroblast generation is sensed and transmitted remains to be determined. As transient receptor potential vanilloid 4 (TRPV4) ion channels are activated by plasma membrane stretch/matrix stiffness, the authors investigated whether TRPV4 plays a role in myofibroblast differentiation and/or in vivo lung fibrosis. TRPV4 inhibition by small-molecule inhibitors almost completely abrogated both the calcium influx response to TPRV4 agonist in a dose-dependent manner and the myofibroblast differentiation response to transforming growth factor-β. Similar findings were noted on TRPV4 deletion with small interfering RNA or in TRPV4 KO murine lung fibroblasts. Mechanistically, TRPV4 activity modulates transforming growth factor b actions in a Smad-independent manner, in part through enhanced actomyosin remodeling with resultant nuclear translocation of the α-smooth muscle actin transcription coactivator. The myofibroblast differentiation response to actual fibrotic lung tissue was also completely inhibited on TRPV4 blockade.