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Basic Research
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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, Andrew Advani, Rohan John, Jeffrey L. Wrana, Andras Kapus and Darren A. Yuen
JASN October 2016, 27 (10) 3117-3128; DOI: https://doi.org/10.1681/ASN.2015050499
Stephen G. Szeto
*Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada; and
†Institute of Medical Science and
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Masahiro Narimatsu
‡Center for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital and Department of Molecular Genetics,
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Mingliang Lu
*Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada; and
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Xiaolin He
*Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada; and
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Ahmad M. Sidiqi
*Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada; and
†Institute of Medical Science and
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Monica F. Tolosa
*Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada; and
§Department of Laboratory Medicine and Pathobiology, School of Graduate Studies,
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Lauren Chan
*Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada; and
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Krystale De Freitas
*Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada; and
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Janne Folke Bialik
*Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada; and
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Syamantak Majumder
*Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada; and
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Stellar Boo
‖Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, and
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Boris Hinz
‖Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, and
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Qinghong Dan
*Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada; and
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Andrew Advani
*Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada; and
†Institute of Medical Science and
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Rohan John
¶Department of Laboratory Medicine and Pathobiology, University Health Network, University of Toronto, Toronto, Ontario, Canada
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Jeffrey L. Wrana
‡Center for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital and Department of Molecular Genetics,
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Andras Kapus
*Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada; and
†Institute of Medical Science and
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Darren A. Yuen
*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,
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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.

  • chronic kidney disease
  • extracellular matrix
  • fibrosis
  • TGF-beta
  • YAP
  • TAZ
  • Copyright © 2016 by the American Society of Nephrology
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Journal of the American Society of Nephrology: 27 (10)
Journal of the American Society of Nephrology
Vol. 27, Issue 10
October 2016
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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, Andrew Advani, Rohan John, Jeffrey L. Wrana, Andras Kapus, Darren A. Yuen
JASN Oct 2016, 27 (10) 3117-3128; DOI: 10.1681/ASN.2015050499

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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, Andrew Advani, Rohan John, Jeffrey L. Wrana, Andras Kapus, Darren A. Yuen
JASN Oct 2016, 27 (10) 3117-3128; DOI: 10.1681/ASN.2015050499
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Keywords

  • chronic kidney disease
  • extracellular matrix
  • fibrosis
  • TGF-beta
  • YAP
  • TAZ

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