| First Author | Sharma S | Year | 2019 |
| Journal | J Cell Mol Med | Volume | 23 |
| Issue | 2 | Pages | 761-774 |
| PubMed ID | 30450767 | Mgi Jnum | J:289495 |
| Mgi Id | MGI:6437030 | Doi | 10.1111/jcmm.13972 |
| Citation | Sharma S, et al. (2019) TRPV4 regulates matrix stiffness and TGFbeta1-induced epithelial-mesenchymal transition. J Cell Mol Med 23(2):761-774 |
| abstractText | Substrate stiffness (or rigidity) of the extracellular matrix has important functions in numerous pathophysiological processes including fibrosis. Emerging data support a role for both a mechanical signal, for example, matrix stiffness, and a biochemical signal, for example, transforming growth factor beta1 (TGFbeta1), in epithelial-mesenchymal transition (EMT), a process critically involved in fibrosis. Here, we report evidence showing that transient receptor potential vanilloid 4 (TRPV4), a mechanosensitive channel, is the likely mediator of EMT in response to both TGFbeta1 and matrix stiffness. Specifically, we found that: (a) genetic ablation or pharmacological inhibition of TRPV4 blocked matrix stiffness and TGFbeta1-induced EMT in normal mouse primary epidermal keratinocytes (NMEKs) as determined by changes in morphology, adhesion, migration and alterations of expression of EMT markers including E-cadherin, N-cadherin (NCAD) and alpha-smooth muscle actin (alpha-SMA), and (b) TRPV4 deficiency prevented matrix stiffness-induced EMT in NMEKs over a pathophysiological range. Intriguingly, TRPV4 deletion in mice suppressed expression of mesenchymal markers, NCAD and alpha-SMA, in a bleomycin-induced murine skin fibrosis model. Mechanistically, we found that: (a) TRPV4 was essential for the nuclear translocation of YAP/TAZ (yes-associated protein/transcriptional coactivator with PDZ-binding motif) in response to matrix stiffness and TGFbeta1, (b) TRPV4 deletion inhibited both matrix stiffness- and TGFbeta1-induced expression of YAP/TAZ proteins and (c) TRPV4 deletion abrogated both matrix stiffness- and TGFbeta1-induced activation of AKT, but not Smad2/3, suggesting a mechanism by which TRPV4 activity regulates EMT in NMEKs. Altogether, these data identify a novel role for TRPV4 in regulating EMT. |
