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Yap/Taz Deletion in Gli+ Cell-Derived Myofibroblasts Attenuates Fibrosis
Ming Liang1,2, Michael Yu2, Ruohan Xia2
1Department of Nephrology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China; and.
Abstract:
In damaged kidneys, increased extracellular matrix (ECM) and tissue stiffness stimulate kidney fibrosis through incompletely characterized molecular mechanisms. The transcriptional coactivators yes-associated protein (Yap) and transcriptional coactivator with PDZ-binding motif (Taz) function as mechanosensors in cancer cells and have been implicated in the regulation of myofibroblasts in the kidney. We hypothesized that the development of kidney fibrosis depends on Yap-induced activation and proliferation of kidney fibroblasts. In mice, Yap expression increased in renal fibroblasts after unilateral ureteral obstruction (UUO), in association with worsening of interstitial fibrosis. In cultured fibroblasts, inhibition of Yap/Taz signaling blocked TGF-β1-induced fibroblast-to-myofibroblast transformation and ECM production, whereas constitutive activation of Yap promoted fibroblast transformation and ECM production even in the absence of TGF-β1. Moreover, in the absence of TGF-β1, fibroblasts seeded on a stiffened ECM transformed into myofibroblasts in a process dependent on the activation of Yap. In mice with UUO, the Yap inhibitor verteporfin reduced interstitial fibrosis. Furthermore, Gli1+ cell-specific knockout of Yap/Taz in mice suppressed UUO-induced ECM deposition, myofibroblast accumulation, and interstitial fibrosis. In a UUO-release model, induction of Gli1+ cell-specific Yap/Taz knockout partially reversed the development of interstitial fibrosis. Thus, in the kidney, Yap is a tissue mechanosensor that can be activated by ECM and transforms fibroblasts into myofibroblasts; the interaction of Yap/Taz and ECM forms a feed-forward loop resulting in kidney fibrosis. Identifying mechanisms that interrupt this profibrotic cycle could lead to the development of anti-fibrosis therapy.
Insights
Kidney fibrosis is driven by tissue stiffness activating the mechanosensor Yap (yes-associated protein), which transforms fibroblasts into myofibroblasts. Targeting this Yap-ECM interaction offers potential anti-fibrosis therapies.
Area of Science:
- Nephrology
- Molecular Biology
- Biomedical Engineering
Background:
- Kidney fibrosis, characterized by increased extracellular matrix (ECM) and tissue stiffness, arises from incompletely understood molecular pathways.
- The transcriptional coactivators Yap (yes-associated protein) and Taz (transcriptional coactivator with PDZ-binding motif) are known mechanosensors implicated in kidney myofibroblast regulation.
Purpose of the Study:
- To investigate the hypothesis that kidney fibrosis development is dependent on Yap-induced activation and proliferation of kidney fibroblasts.
- To elucidate the role of Yap as a tissue mechanosensor in kidney fibrosis.
Main Methods:
- Utilized mouse models of unilateral ureteral obstruction (UUO) and a UUO-release model.
- Employed cultured fibroblasts, Yap/Taz signaling inhibition (verteporfin), and Gli1+-cell-specific Yap/Taz knockout.
- Assessed fibroblast-to-myofibroblast transformation, ECM production, and interstitial fibrosis.
Main Results:
- Yap expression increased in renal fibroblasts post-UUO, correlating with interstitial fibrosis.
- Inhibition of Yap/Taz signaling blocked TGF-β1-induced fibroblast activation and ECM production.
- Constitutive Yap activation promoted fibroblast transformation and ECM production independently of TGF-β1.
- Fibroblasts on stiff ECM transformed into myofibroblasts via Yap activation, even without TGF-β1.
- Verteporfin treatment and Yap/Taz knockout in mice reduced or reversed UUO-induced fibrosis, ECM deposition, and myofibroblast accumulation.
Conclusions:
- Yap acts as a critical kidney mechanosensor activated by ECM, driving fibroblast-to-myofibroblast transformation and contributing to kidney fibrosis.
- A feed-forward loop between Yap/Taz and ECM promotes kidney fibrosis.
- Targeting the Yap-ECM interaction presents a potential therapeutic strategy for anti-fibrosis treatments.
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