YAP/TAZ Are Mechanoregulators of TGF-β-Smad Signaling and... : Journal of the American Society of Nephrology (original) (raw)

Basic Research

Szeto, Stephen G.*,†; Narimatsu, Masahiro‡; Lu, Mingliang*; He, Xiaolin*; Sidiqi, Ahmad M.*,†; Tolosa, Monica F.*,§; Chan, Lauren*; De Freitas, Krystale*; Bialik, Janne Folke*; Majumder, Syamantak*; Boo, Stellar‖; Hinz, Boris‖; Dan, Qinghong*; Advani, Andrew*,†; John, Rohan¶; Wrana, Jeffrey L.‡; Kapus, Andras*,†; Yuen, Darren A.*,†,§

*Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada; and

†Institute of Medical Science and

§Department of Laboratory Medicine and Pathobiology, School of Graduate Studies,

‡Center for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital and Department of Molecular Genetics,

‖Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, and

¶Department of Laboratory Medicine and Pathobiology, University Health Network, University of Toronto, Toronto, Ontario, Canada

Correspondence: Dr. Darren A. Yuen, Room 509, 5th Floor, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, 209 Victoria Street, Toronto, ON M5B 1T8, Canada. Email: [email protected]

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.