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YAP/TAZ Are Mechanoregulators of TGF-β-Smad Signaling and Renal Fibrogenesis

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dc.contributor.author Majumder, Syamantak
dc.date.accessioned 2021-10-02T17:47:48Z
dc.date.available 2021-10-02T17:47:48Z
dc.date.issued 2016-10
dc.identifier.uri https://jasn.asnjournals.org/content/27/10/3117
dc.identifier.uri http://dspace.bits-pilani.ac.in:8080/xmlui/handle/123456789/2418
dc.description.abstract Like many organs, the kidney stiffens after injury, a process that is increasingly recognized as an important driver of fibrogenesis. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are related mechanosensory proteins that bind to Smad transcription factors, the canonical mediators of profibrotic TGF-β responses. Here, we investigated the role of YAP/TAZ in the matrix stiffness dependence of fibroblast responses to TGF-β. In contrast to growth on a stiff surface, fibroblast growth on a soft matrix led to YAP/TAZ sequestration in the cytosol and impaired TGF-β–induced Smad2/3 nuclear accumulation and transcriptional activity. YAP knockdown or treatment with verteporfin, a drug that was recently identified as a potent YAP inhibitor, elicited similar changes. Furthermore, verteporfin reduced YAP/TAZ levels and decreased the total cellular levels of Smad2/3 after TGF-β stimulation. Verteporfin treatment of mice subjected to unilateral ureteral obstruction similarly reduced YAP/TAZ levels and nuclear Smad accumulation in the kidney, and attenuated renal fibrosis. Our data suggest that organ stiffening cooperates with TGF-β to induce fibrosis in a YAP/TAZ- and Smad2/3-dependent manner. Interference with this YAP/TAZ and TGF-β/Smad crosstalk likely underlies the antifibrotic activity of verteporfin. Finally, through repurposing of a clinically used drug, we illustrate the therapeutic potential of a novel mechanointerference strategy that blocks TGF-β signaling and renal fibrogenesis. en_US
dc.language.iso en en_US
dc.publisher JASN en_US
dc.subject Biology en_US
dc.subject Chronic kidney disease en_US
dc.subject Extracellular matrix en_US
dc.subject Fibrosis en_US
dc.subject TGF-beta en_US
dc.subject YAP en_US
dc.title YAP/TAZ Are Mechanoregulators of TGF-β-Smad Signaling and Renal Fibrogenesis en_US
dc.type Article en_US


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