TY - JOUR AU - Rahaman, Shaik O. AU - Grove, Lisa M. AU - Paruchuri, Sailaja AU - Southern, Brian D. AU - Abraham, Susamma AU - Niese, Kathryn A. AU - Scheraga, Rachel G. AU - Ghosh, Sudakshina AU - Thodeti, Charles K. AU - Zhang, David X. AU - Moran, Magdalene M. AU - Schilling, William P. AU - Tschumperlin, Daniel J. AU - Olman, Mitchell A. T1 - TRPV4 mediates myofibroblast differentiation and pulmonary fibrosis in mice PY - 2014/12/01/ AB - Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disorder with no effective medical treatments available. The generation of myofibroblasts, which are critical for fibrogenesis, requires both a mechanical signal and activated TGF-β; however, it is not clear how fibroblasts sense and transmit the mechanical signal(s) that promote differentiation into myofibroblasts. As transient receptor potential vanilloid 4 (TRPV4) channels are activated in response to changes in plasma membrane stretch/matrix stiffness, we investigated whether TRPV4 contributes to generation of myofibroblasts and/or experimental lung fibrosis. We determined that TRPV4 activity is upregulated in lung fibroblasts derived from patients with IPF. Moreover, TRPV4-deficient mice were protected from fibrosis. Furthermore, genetic ablation or pharmacological inhibition of TRPV4 function abrogated myofibroblast differentiation, which was restored by TRPV4 reintroduction. TRPV4 channel activity was elevated when cells were plated on matrices of increasing stiffness or on fibrotic lung tissue, and matrix stiffness–dependent myofibroblast differentiation was reduced in response to TRVP4 inhibition. TRPV4 activity modulated TGF-β1–dependent actions in a SMAD-independent manner, enhanced actomyosin remodeling, and increased nuclear translocation of the α-SMA transcription coactivator (MRTF-A). Together, these data indicate that TRPV4 activity mediates pulmonary fibrogenesis and suggest that manipulation of TRPV4 channel activity has potential as a therapeutic approach for fibrotic diseases. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI75331 VL - 124 IS - 12 UR - https://doi.org/10.1172/JCI75331 SP - 5225 EP - 5238 PB - The American Society for Clinical Investigation ER -