The DOI matches its Crossref record; 59 of the 60 references it cites were found in a registry or an index.
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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Raghu, G., Collard, H. R., Egan, J. J., Martinez, F. J., Behr, J., Brown, K. K., Colby, T. V., Cordier, J.-F., Flaherty, K. R., Lasky, J. A., et al. (2011) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.2009-040gl · Cited by 7,186
Calcium signalling: dynamics, homeostasis and remodelling
Berridge, M. J., Bootman, M. D., & Roderick, H. L. (2003) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1155 · Cited by 5,719
Mechanisms of fibrosis: therapeutic translation for fibrotic disease
Wynn, T. A., & Ramalingam, T. R. (2012) · Nature Medicine · doi:10.1038/nm.2807 · Cited by 3,541
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Venkatachalam, K., & Montell, C. (2007) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.75.103004.142819 · Cited by 1,996
Prednisone, Azathioprine, and N -Acetylcysteine for Pulmonary Fibrosis
The Idiopathic Pulmonary Fibrosis Clinical Research Network (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1113354 · Cited by 1,654
Targeting the TGFβ signalling pathway in disease
Akhurst, R. J., & Hata, A. (2012) · Nature Reviews Drug Discovery · doi:10.1038/nrd3810 · Cited by 1,466
Biernacka, A., Dobaczewski, M. P., & Frangogiannis, N. G. (2011) · Growth Factors · doi:10.3109/08977194.2011.595714 · Cited by 1,205
Recent Developments in Myofibroblast Biology
Hinz, B., Phan, S. H., Thannickal, V. J., Prunotto, M., Desmoulière, A., Varga, J., De Wever, O., Mareel, M., & Gabbiani, G. (2012) · The American Journal of Pathology · doi:10.1016/j.ajpath.2012.02.004 · Cited by 1,193
Efficacy of a Tyrosine Kinase Inhibitor in Idiopathic Pulmonary Fibrosis
Richeldi, L., Costabel, U., Selman, M., Kim, D. S., Hansell, D. M., Nicholson, A. G., Brown, K. K., Flaherty, K. R., Noble, P. W., Raghu, G., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1103690 · Cited by 1,157
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1 of the 60 references couldn’t be matched to a known paper.
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- Zhu MX, ed. TRP Channels. Boca Raton, Florida, USA: CRC Press; 2011.
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Items 301–308 of 308
Potential role of the Trpv4 c.1491+1G>A mutation in pulmonary fibrosis in a gene-edited mouse model
Ruan, H., Wang, H., Zhu, C., Li, Z., ASu, Y., Ji, Z., Li, Y., Gu, L., Fu, C., Yu, H., et al. (2026) · Frontiers in Genetics · doi:10.3389/fgene.2026.1834091
TRPV4: A Promising Therapeutic Target Ion Channel─Discovery of Ultrapotent Selective Antagonists
Nilsson, M., Bonvini, S. J., Diers, E., Johansson, J., Lawrence, N., Andersson, H., von Berg, S., Berglund, S., Birrell, M. A., Bold, P., et al. (2026) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6c00672
Kanrar, M., & Das, A. (2026) · IEEE International Conference on Intelligent Technologies for a Sustainable and Inclusive Future (ICITSIF) · doi:10.1109/icitsif69060.2026.11608780
Liu, S., Dong, S., Gong, L., Yang, J., Liu, H., Piao, M., Wu, Y., An, H., Zhang, L., & Yu, J. (2026) · Inflammation Research · doi:10.1007/s00011-026-02327-1
Conversations in collagen: multicellular cross talk shapes the fibrotic niche in pulmonary fibrosis
Salamon, R. J., & Saini, S. (2026) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00426.2025
Song, C., Jeong, Y., & Kim, T. (2026) · Animal Cells and Systems · doi:10.1080/19768354.2026.2677272
Soft tissue mechanosensing and remodeling: the core regulatory role of Piezo/TRPV4 ion channels
Fan, X., Shi, M., Wang, Z., Zhao, C., Zhao, Y., Zhou, Y., & Xu, H. (2026) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2026.1869360
Lonardo, A., & Weiskirchen, R. (2026) · Journal of Cell Communication and Signaling · doi:10.1002/ccs3.70111
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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