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

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

Stephen G Szeto, Masahiro Narimatsu, Mingliang Lu, Xiaolin He, Ahmad M Sidiqi, Monica F Tolosa, Lauren Chan, Krystale De Freitas, Janne Folke Bialik, Syamantak Majumder, Stellar Boo, Boris Hinz, Qinghong Dan, etc.

J Am Soc Nephrol. 2016 Oct;27(10):3117-3128.

PMID: 26961347

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP129497785	Verteporfin		129497-78-5	Price

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