title: YAP/TAZ Are Mechanoregulators of TGF-β-Smad Signaling and Renal Fibrogenesis.
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-βresponses. Here, we investigated the role of YAP/TAZ in the matrix stiffness dependence of fibroblast responses to TGF-βIn 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-βstimulation. 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-βto 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-βsignaling and renal fibrogenesis.
authors.affiliation: Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada; and.|Institute of Medical Science and.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Szeto
authors.affiliation: Center for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital and Department of Molecular Genetics.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Narimatsu
authors.affiliation: Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada; and.
authors.forename: Mingliang
authors.initials: M
authors.lastname: Lu
authors.affiliation: Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada; and.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: He
authors.affiliation: Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada; and.|Institute of Medical Science and.
authors.forename: Ahmad M
authors.initials: AM
authors.lastname: Sidiqi
authors.affiliation: 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.
authors.forename: Monica F
authors.initials: MF
authors.lastname: Tolosa
authors.affiliation: Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada; and.
authors.forename: Lauren
authors.initials: L
authors.lastname: Chan
authors.affiliation: Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada; and.
authors.forename: Krystale
authors.initials: K
authors.lastname: De Freitas
authors.affiliation: Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada; and.
authors.forename: Janne Folke
authors.initials: JF
authors.lastname: Bialik
authors.affiliation: Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada; and.
authors.forename: Syamantak
authors.initials: S
authors.lastname: Majumder
authors.affiliation: Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, and.
authors.forename: Stellar
authors.initials: S
authors.lastname: Boo
authors.affiliation: Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, and.
authors.forename: Boris
authors.initials: B
authors.lastname: Hinz
authors.affiliation: Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada; and.
authors.forename: Qinghong
authors.initials: Q
authors.lastname: Dan
authors.affiliation: Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada; and.|Institute of Medical Science and.
authors.forename: Andrew
authors.initials: A
authors.lastname: Advani
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University Health Network, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Rohan
authors.initials: R
authors.lastname: John
authors.affiliation: Center for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital and Department of Molecular Genetics.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Wrana
authors.affiliation: Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada; and.|Institute of Medical Science and.
authors.forename: Andras
authors.initials: A
authors.lastname: Kapus
authors.affiliation: Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada; and darren.yuen@utoronto.ca.|Institute of Medical Science and.|Department of Laboratory Medicine and Pathobiology, School of Graduate Studies.
authors.forename: Darren A
authors.initials: DA
authors.lastname: Yuen
mesh_terms: D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D018797:Cell Cycle Proteins; D005355:Fibrosis / Q000209:etiology; D007668:Kidney / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010750:Phosphoproteins / Q000502:physiology*; D015398:Signal Transduction; D051899:Smad2 Protein / Q000502:physiology*; D051900:Smad3 Protein / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D000217:Acyltransferases; C486363:tafazzin protein, mouse
keywords: TAZ; TGF-beta; YAP; chronic kidney disease; extracellular matrix; fibrosis