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TRPV4 mediates myofibroblast differentiation and pulmonary fibrosis in mice
Open accessAbstract
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.
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“TRPV4 channel activation leads to calcium influx, which subsequently activates MAPK and NF-kB pathways to drive myofibroblast differentiation and ECM accumulation (134).”
From The mechanotransduction-immune axis in organ fibrosis: dual regulatory mechanisms and translational therapeutic perspectives (2025) · cites this paper as [134]
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Metadata
- Authors
- Rahaman, S. O., Grove, L. M., Paruchuri, S., Southern, B. D., Abraham, S., Niese, K. A., Scheraga, R. G., Ghosh, S., Thodeti, C. K., Zhang, D. X., Moran, M. M., Schilling, W. P., Tschumperlin, D. J., & Olman, M. A.
- Affiliations
- Cleveland Clinic (US)
- Northeast Ohio Medical University (US)
- Medical College of Wisconsin (US)
- MetroHealth Medical Center (US)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2014-11-03
- Volume
- 124
- Issue
- 12
- Pages
- 5225-5238
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC4348970
- OpenAlex
- W2093726551
- Cited by
- 310
- References
- 60
- Citations by year
- 2026: 29 · 2025: 31 · 2024: 25 · 2023: 18 · 2022: 45 · 2021: 31 · 2020: 31 · 2019: 17 · 2018: 21 · 2017: 23 · 2016: 21 · 2015: 18
- FWCI
- 16.58
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL103553, R01HL096647, R01HL119792, R01HL085324)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pulmonary Hypertension Research and Treatments
- Keywords
- TRPV4, myofibroblast differentiation, pulmonary fibrosis, idiopathic pulmonary fibrosis, mechanotransduction, extracellular matrix stiffness, TGF-β1 signaling, Smad-independent signaling, MRTF-A, lung fibroblasts
- MeSH terms
- Animals, Antibiotics, Antineoplastic, Bleomycin, Cell Differentiation, Extracellular Matrix, Female, Lung, Mice, Mutant Strains, Pulmonary Fibrosis, Trans-Activators, Up-Regulation, TRPV Cation Channels, Mice, Transforming Growth Factor beta1, Myofibroblasts
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