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-b responses. Here, we investigated the role of YAP/TAZ in the matrix stiffness dependence of fibroblast responses to TGF-b. 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-b-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-b 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-b to induce fibrosis in a YAP/TAZ-and Smad2/3-dependent manner. Interference with this YAP/TAZ and TGF-b/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-b signaling and renal fibrogenesis.

Sav1 Loss Induces Senescence and Stat3 Activation Coinciding with Tubulointerstitial Fibrosis

“…Verteporfin (Visudyn; Novartis) is currently an FDA-approved drug administered intravenously to patients in photodynamic therapy to treat macular degeneration with minimal side effects. Our findings are consistent with recently published work showing the efficacy of VP for inhibiting Yap activity and renal fibrosis induced by UUO (65). Collectively, these results bring to light the potential for VP as a candidate pharmacological inhibitor to be administered to patients who may be at increased risk for AKI and subsequent renal fibrosis as a result of their existing medical condition or specific medical procedures and treatments which they are about to undergo (i.e., surgery, chemotherapy, etc.).…”

Human pericytes adopt myofibroblast properties in the microenvironment of the IPF lung

“…For example, focal adhesions and focal adhesion kinases (FAK) play an integral part of α-SMA expression in fibroblast-to-myofibroblast transdifferentiation (31) as a means of signal transduction from clustered integrin-ligand binding interactions between cells and the fibrotic ECM. Additionally, immunostaining of fibroblasts grown on fibronectin-coated gels with varying stiffness revealed an increase in nuclear translocation of yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) in fibroblasts seeded on stiffer substrates (32). A YAP/TAZ-dependent mechanism in PC following TGF-β1 activation has yet to be deter- (B-D) Matrix deposition was quantified using immunoblotting (n = 7), and (E) fibrotic lesions were quantified from images (n ≥ 10) at day 28 (represented as mean ± SEM, Student t test with Bonferroni post-test, *P < 0.05 versus TGF-β1).…”

YAP/TAZ Are Essential for TGF-β2–Mediated Conjunctival Fibrosis

“…Taken together, these results suggest that YAP, but not TAZ, is required for TGF-b2-induced Smad2/3 signaling in human primary conjunctival fibroblasts. We next examined the effects of a potent YAP/TAZ inhibitor, verteporfin, 20 on the TGF-b2-induced fibrotic changes in conjunctival fibroblasts. Verteporfin reduced YAP/TAZ levels in a dose-dependent manner, and moreover, verteporfin reduced the level of TEAD1 (Fig.…”