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TRPV4 mediates myofibroblast differentiation and pulmonary fibrosis in mice. J Clin Invest 2014 Dec;124(12):5225-38

Date

11/05/2014

Pubmed ID

25365224

Pubmed Central ID

PMC4348970

DOI

10.1172/JCI75331

Scopus ID

2-s2.0-84915748921   104 Citations

Abstract

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.

Author List

Rahaman SO, Grove LM, Paruchuri S, Southern BD, Abraham S, Niese KA, Scheraga RG, Ghosh S, Thodeti CK, Zhang DX, Moran MM, Schilling WP, Tschumperlin DJ, Olman MA

Author

David X. Zhang MD, PhD Associate Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Antibiotics, Antineoplastic
Bleomycin
Cell Differentiation
Extracellular Matrix
Female
Lung
Mice
Mice, Mutant Strains
Myofibroblasts
Pulmonary Fibrosis
TRPV Cation Channels
Trans-Activators
Transforming Growth Factor beta1
Up-Regulation
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a