TRPV4 ION Channel Is Associated with Scleroderma

Goswami, Rishov; Cohen, Jonathan; Sharma, Shweta; Zhang, David X.; Lafyatis, Robert; Bhawan, Jag; Rahaman, Shaik O.

doi:10.1016/j.jid.2016.10.045

Cited by 27 publications

(51 citation statements)

References 15 publications

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“…Transforming growth factor β1 is known to induce EMT in keratinocytes . Recent evidence from our group suggests a link between TRPV4 activation and TGFβ1 signals that mediate fibroblast differentiation . Previous reports have documented that calcium signalling is involved in EMT in many cell types .…”

Section: Resultsmentioning

confidence: 86%

“…We previously reported that TRPV4 KO mice are protected from pro‐fibrotic effects of bleomycin in lung and skin, and bleomycin has been shown to cause EMT in skin and pulmonary fibrosis model . To determine whether TRPV4 deficiency could also suppress EMT in an experimental model of skin fibrosis, we employed the bleomycin‐induced skin fibrosis model, and analysed expression of EMT markers between bleomycin or phosphate‐buffered saline (PBS) treated TRPV4 KO and WT mice.…”

Section: Resultsmentioning

confidence: 99%

“…Bleomycin‐induced fibrosis is a well‐recognized model of fibrotic diseases including skin and lung fibrosis where matrix is stiffened in a progressive manner . Several lines of evidence support the role of EMT in bleomycin induced lung fibrosis .…”

Section: Discussionmentioning

confidence: 99%

“…Recently, we reported that transient receptor potential vanilloid 4 (TRPV4), a mechanosensitive Ca 2+ ‐permeable channel, is associated with skin and lung fibrosis. TRPV4 regulates both biochemical (TGFβ1)‐ and mechanical (matrix stiffness) stimulus‐induced lung and dermal myofibroblast differentiation and contributes to the development of in vivo pulmonary and skin fibrosis in murine models . However, the specific role of TRPV4 in EMT in normal primary epidermal keratinocytes has not been determined.…”

Section: Introductionmentioning

confidence: 99%

“…TRPV4 was shown to function as a mechanosensor in response to cyclical stretching of cells, mechanical forces applied to β1 integrins in cell surface or dynamic loading in chondrocytes . Structurally, TRPV4 contains a number of potential regulatory domains and protein‐interaction sites, including phosphoinositide 3‐kinase (PI3K) and Src homology 2 recognition domains, putative protein kinase C phosphorylation sites, PDZ domains and an N‐terminal ankyrin repeat region . Numerous mutations in TRPV4 have been associated with human diseases including skeletal dysplasia and sensory and motor neuropathies .…”

Section: Introductionmentioning

confidence: 99%

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TRPV4 regulates matrix stiffness and TGFβ1‐induced epithelial‐mesenchymal transition

Sharma

Goswami

Zhang

et al. 2018

J Cellular Molecular Medi

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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 β1 (TGFβ1), 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 TGFβ1 and matrix stiffness. Specifically, we found that: (a) genetic ablation or pharmacological inhibition of TRPV4 blocked matrix stiffness and TGFβ1‐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 α‐smooth muscle actin (α‐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 α‐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 TGFβ1, (b) TRPV4 deletion inhibited both matrix stiffness‐ and TGFβ1‐induced expression of YAP/TAZ proteins and (c) TRPV4 deletion abrogated both matrix stiffness‐ and TGFβ1‐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.

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Section: Resultsmentioning

confidence: 86%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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TRPV4 regulates matrix stiffness and TGFβ1‐induced epithelial‐mesenchymal transition

Sharma

Goswami

Zhang

et al. 2018

J Cellular Molecular Medi

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Management of experimental trabeculectomy filtering blebs via crosslinking of the scleral flap inhibited vascularization

Ge,

Wu,

Liu

et al. 2023

Graefes Arch Clin Exp Ophthalmol

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Role of TRPV4 in matrix stiffness-induced expression of EMT-specific LncRNA

Sharma

Rahaman

2020

Mol Cell Biochem

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Long non-coding RNAs (LncRNAs) are long (>200 bases), non-coding, single-stranded RNAs that have emerged as major regulators of gene expression, cell differentiation, development, and oncogenesis. In view of the fact that matrix stiffness plays a role in cellular functions associated with these processes, it is important to ask what role matrix stiffness plays in regulating expression of LncRNAs. In this report, we show that i) matrix stiffness causes differential expression of epithelial-mesenchymal transition (EMT)-related LncRNAs and mRNAs in primary mouse normal epidermal keratinocytes, ii) differential expression of EMT-related LncRNAs and mRNAs occurs in response to combined stimulation of transforming growth factor β1 and matrix stiffness, and iii) transient receptor potential (TRP) channel of the vanilloid subfamily, TRPV4, a matrix stiffnesssensitive ion channel, plays a role in differential expression of EMT-related LncRNAs and mRNAs in response to combined stimulation by TGFβ1 and matrix stiffness. These data identify TRPV4 as a candidate plasma membrane mechanosensor that transmits matrix-sensing signals essential to LncRNA expression. Our results also show that we have established and validated an assay system capable of discovering novel LncRNAs and mRNAs sensitive to matrix stiffening.

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TRPV4 ION Channel Is Associated with Scleroderma

Abstract: Critical evaluation of two primers commonly used for amplification of bacterial 16S rRNA genes. Appl Environ Microbiol 2008;74:2461e70. Kong HH. Details matter: designing skin microbiome studies. J Invest Dermatol 2016;136: 900e2.

Cited by 27 publications

References 15 publications

TRPV4 regulates matrix stiffness and TGFβ1‐induced epithelial‐mesenchymal transition

TRPV4 regulates matrix stiffness and TGFβ1‐induced epithelial‐mesenchymal transition

Management of experimental trabeculectomy filtering blebs via crosslinking of the scleral flap inhibited vascularization

Role of TRPV4 in matrix stiffness-induced expression of EMT-specific LncRNA

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