Myofibroblast YAP/TAZ activation is a key step in organ fibrogenesis

He, Xiaolin; Tolosa, Monica F.; Zhang, Tianzhou; Goru, Santosh Kumar; Severino, Luisa Ulloa; Misra, Paraish S.; McEvoy, Caitríona M.; Caldwell, Lauren; Szeto, Stephen G.; Gao, Feng; Chen, Xiaolan; Atin, Cassandra; Ki, Victoria; Vukosa, Noah; Hu, Catherine; Zhang, Johnny; Yip, Christopher M.; Krizova, Adriana; Wrana, Jeffrey L.; Yuen, Darren A.

doi:10.1172/jci.insight.146243

Cited by 41 publications

(25 citation statements)

References 66 publications

(100 reference statements)

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“…In this retrospective case control study, we analyzed a convenience sample of 18 archived human transplant kidney biopsies stored in the Department of Laboratory Medicine and Pathobiology at St. Michael’s Hospital ( 57 ). The inclusion criteria were as follows: (i) Kidneys must have been transplanted >1 year prior, and (ii) sufficient tissue is needed to be available for RNA-seq.…”

Section: Methodsmentioning

confidence: 99%

“…Details of data collection are provided in the Supplementary Materials. RNA sequencing RNA was extracted from kidney biopsy tissue, and complementary DNA (cDNA) libraries were prepared and sequenced on an Illumina HiSeq 2000 or 3000 (57), as described in the Supplementary Materials. RNA yield, read numbers per sample, and other relevant data are summarized in table S4.…”

Section: Human Kidney Biopsy Studymentioning

confidence: 99%

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NUAK1 promotes organ fibrosis via YAP and TGF-β/SMAD signaling

Zhang

Caldwell

et al. 2022

Sci. Transl. Med.

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Fibrosis is a central pathway that drives progression of multiple chronic diseases, yet few safe and effective clinical antifibrotic therapies exist. In most fibrotic disorders, transforming growth factor–β (TGF-β)–driven scarring is an important pathologic feature and a key contributor to disease progression. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are two closely related transcription cofactors that are important for coordinating fibrogenesis after organ injury, but how they are activated in response to tissue injury has, so far, remained unclear. Here, we describe NUAK family kinase 1 (NUAK1) as a TGF-β–inducible profibrotic kinase that is up-regulated in multiple fibrotic organs in mice and humans. Mechanistically, we show that TGF-β induces a rapid increase in NUAK1 in fibroblasts. NUAK1, in turn, can promote profibrotic YAP and TGF-β/SMAD signaling, ultimately leading to organ scarring. Moreover, activated YAP and TAZ can induce further NUAK1 expression, creating a profibrotic positive feedback loop that enables persistent fibrosis. Using mouse models of kidney, lung, and liver fibrosis, we demonstrate that this fibrogenic signaling loop can be interrupted via fibroblast-specific loss of NUAK1 expression, leading to marked attenuation of fibrosis. Pharmacologic NUAK1 inhibition also reduced scarring, either when initiated immediately after injury or when initiated after fibrosis was already established. Together, our data suggest that NUAK1 plays a critical, previously unrecognized role in fibrogenesis and represents an attractive target for strategies that aim to slow fibrotic disease progression.

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Section: Methodsmentioning

confidence: 99%

Section: Human Kidney Biopsy Studymentioning

confidence: 99%

NUAK1 promotes organ fibrosis via YAP and TGF-β/SMAD signaling

Zhang

Caldwell

et al. 2022

Sci. Transl. Med.

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“…However, verteporfin treatment inhibited TGF-βinduced Smad activation and thereby impaired UUO-induced renal fibrosis and fibroblasts activation in cultured cells [17]. Myofibroblast-specific ablation of YAP/TAZ attenuated kidney fibrosis, while myofibroblast-specific deletion of LATS1 and LATS2 promoted YAP/TAZ activation in myofibroblasts and aggravated fibrosis [40].…”

Section: Hippo Signaling Pathway In Renal Fibrosismentioning

confidence: 98%

“…As such, treatment of mice with an MST1/2 blocker XMU-MP-1 inhibits pressure-induced cardiac hypertrophy and fibrosis (Table 1) [39]. Similarly, LATS1/2-mutant cardiac fibroblasts are less prone to develop into fibrotic phenotype after infarction-induced injury [35], while deletion of LATS1/2 stimulates YAP/TAZ activation in myofibroblasts and aggravates kidney fibrosis [40]. Similarly, genetic inactivation of SAV1 in renal tubule cells promotes renal interstitial fibrosis [36].…”

Section: Introductionmentioning

confidence: 99%

New Insights into Hippo/YAP Signaling in Fibrotic Diseases

Mia

Singh

2022

Cells

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Fibrosis results from defective wound healing processes often seen after chronic injury and/or inflammation in a range of organs. Progressive fibrotic events may lead to permanent organ damage/failure. The hallmark of fibrosis is the excessive accumulation of extracellular matrix (ECM), mostly produced by pathological myofibroblasts and myofibroblast-like cells. The Hippo signaling pathway is an evolutionarily conserved kinase cascade, which has been described well for its crucial role in cell proliferation, apoptosis, cell fate decisions, and stem cell self-renewal during development, homeostasis, and tissue regeneration. Recent investigations in clinical and pre-clinical models has shown that the Hippo signaling pathway is linked to the pathophysiology of fibrotic diseases in many organs including the lung, heart, liver, kidney, and skin. In this review, we have summarized recent evidences related to the contribution of the Hippo signaling pathway in the development of organ fibrosis. A better understanding of this pathway will guide us to dissect the pathophysiology of fibrotic disorders and develop effective tissue repair therapies.

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“…Yes-associated protein (YAP), an effector of the canonical Hippo signaling pathway, can be activated by upstream mechanical signals (such as the increase in matrix stiffness), which promotes its nuclear translocation and targeted gene induction, and has emerged as a crucial factor in the pathogenesis of fibrosis in organs, including the kidney, liver, lung and cardiac tissue (Hu et al, 2021). A recent report confirmed that myofibroblast YAP was activated early and driven to fibrosis in the liver, lung and kidney injury in mice and humans (He et al, 2022). However, although we had profound insights into fibrosis at the cellular and molecular level, and had built different pathogenic models to mimic fibrogenesis, there were few satisfactory therapies and even fewer approaches focusing on mechano-regulation in clinical practice.…”

Section: Introductionmentioning

confidence: 99%

Polydatin attenuates tubulointerstitial fibrosis in diabetic kidney disease by inhibiting YAP expression and nuclear translocation

Feng

Chen

et al. 2022

Front. Physiol.

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The activation of Yes-associated protein (YAP) pathway is mutually causal with the increase of extracellular matrix (ECM) stiffness. Polydatin (PD) has been proved to have anti-fibrosis effect in diabetic kidney disease (DKD), but it is still a mystery whether PD participates in YAP-related mechano-transduction. Therefore, this study intends to solve the following two problems: 1) To construct an in vitro system of polyacrylamide hydrogels (PA gels) based on the true stiffness of kidneys in healthy and DKD rats, and observe the effect of PD on pathological matrix stiffness-induced YAP expression in renal fibroblasts; 2) Compared with verteporfin (VP), a pharmacological inhibitor of YAP, to explore whether the therapeutic effect of PD on DKD in vivo model is related to the regulation of YAP. In this study, the in vitro system of PA gels with 3 kPa, 12 kPa and 30 kPa stiffness was constructed and determined for the first time to simulate the kidney stiffness of healthy rats, rats with DKD for 8 weeks and 16 weeks, respectively. Compared with the PA gels with 3 kPa stiffness, the PA gels with 12 kPa and 30 kPa stiffness significantly increased the expression of YAP, α-smooth muscle actin (α-SMA) and collagen I, and the production of reactive oxygen species (ROS) in renal fibroblasts, and the PA gels with 30 kPa stiffness were the highest. PD significantly inhibited the above-mentioned changes of fibroblasts induced by pathological matrix stiffness, suggesting that the inhibition of PD on fibroblast-to-myofibroblast transformation and ECM production was at least partially associated with regulating YAP-related mechano-transduction pathway. Importantly, the inhibitory effect of PD on YAP expression and nuclear translocation in kidneys of DKD rats is similar to that of VP, but PD is superior to VP in reducing urinary protein, blood glucose, blood urea nitrogen and serum creatinine, as well as decreasing the expression of α-SMA and collagen I, ROS overproduction and renal fibrosis. Our results prove for the first time from the biomechanical point of view that PD is a potential therapeutic strategy for delaying the progression of renal fibrosis by inhibiting YAP expression and nuclear translocation.

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Myofibroblast YAP/TAZ activation is a key step in organ fibrogenesis

Cited by 41 publications

References 66 publications

NUAK1 promotes organ fibrosis via YAP and TGF-β/SMAD signaling

NUAK1 promotes organ fibrosis via YAP and TGF-β/SMAD signaling

New Insights into Hippo/YAP Signaling in Fibrotic Diseases

Polydatin attenuates tubulointerstitial fibrosis in diabetic kidney disease by inhibiting YAP expression and nuclear translocation

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