TRPV4-TAZ signaling in matrix stiffness- and TGFβ1-induced epithelial-mesenchymal transition

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Epithelial-mesenchymal transition (EMT) is an essential event in development, fibrogenesis, and oncogenesis. Emerging data support a role for both a mechanical signal and a biochemical signal, an EMT. Here, we report evidence that transient receptor potential vanilloid 4 (TRPV4), a channel sensitive to both matrix stiffness and transforming growth factor β1 (TGFβ1) stimuli, is a likely mediator of EMT. We found that antagonism of TRPV4 blocked both matrix stiffness- and TGFβ1-induced EMT in normal human primary epidermal keratinocytes, as determined by changes in morphology and alterations in expression of EMT markers including E-cadherin, N-cadherin, and α-smooth muscle actin (α- SMA).

In a murine dermal fibrosis model, TRPV4 deletion resulted in decreased expression of the mesenchymal marker, α-SMA, and increased expression of the epithelial marker, E-cadherin. Furthermore, we found that: i) TRPV4 was essential for the nuclear translocation of TAZ in response to matrix stiffness and TGFβ1; ii) Antagonism of TRPV4 inhibited both matrix stiffness-induced and TGFβ1-induced expression of TAZ proteins; and iii) TRPV4 antagonism suppressed both matrix stiffness-induced and TGFβ1-induced activation of Smad2/3, but not of AKT. Altogether, these data identify a novel role for TRPV4 in regulating EMT in response to both matrix stiffness and TGFβ1.

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 Author: Shaik O. Rahaman, University of Maryland, USA

 International Conference on Wound Care, Tissue Repair and Regenerative MedicineDate & venue: June 14-15, 2018 | London, UKWebsite: https://goo.gl/eLcFyZ

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