Journal
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
Volume 27, Issue 10, Pages 3117-3128Publisher
AMER SOC NEPHROLOGY
DOI: 10.1681/ASN.2015050499
Keywords
-
Categories
Funding
- Natural Sciences and Engineering Research Council Canada Graduate Scholarship
- Queen Elizabeth II Graduate Scholarship in Science and Technology
- Li Ka Shing Knowledge Institute Scholarship
- Canadian Diabetes Association
- Kidney Research Scientist Core Education and National Training Program (KRESCENT) Infrastructure grant
- Kidney Foundation of Canada Biomedical grant [KFOC130031]
- J.P. Bickell Foundation Medical Research grant
- Canadian Institutes of Health Research [201503MOP-341962]
- St. Michael's Hospital Foundation
- KRESCENT New Investigator
- Canadian Diabetes Association Clinician Scientist award
Ask authors/readers for more resources
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-beta responses. Here, we investigated the role of YAP/TAZ in the matrix stiffness dependence of fibroblast responses to TGF-beta. 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-beta-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-beta 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-beta to induce fibrosis in a YAP/TAZ- and Smad2/3-dependent manner. Interference with this YAP/TAZ and TGF-beta/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-beta signaling and renal fibrogenesis.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available