Yap/Taz mediates mTORC2-stimulated fibroblast activation and kidney fibrosis

Gui, Yuan; Li, Jianzhong; Lu, Qingmiao; Feng, Yan; Wang, Mingjie; He, Weichun; Yang, Junwei; Dai, Chunsun

doi:10.1074/jbc.ra118.004073

Cited by 43 publications

(28 citation statements)

References 47 publications

(38 reference statements)

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“…Both mTOR complex 1 (mTORC1) and mTORC2 were activated in UUO kidneys [9,10]. Furthermore, Yap was revealed to mediate mTORC2-induced renal interstitial fibrosis [12]. Increasing evidence indicated that Yap functioned as a pro-fibrotic factor in kidneys, and targeting Yap improved renal interstitial fibrosis [20,37,38,39].…”

Section: Discussionmentioning

confidence: 99%

“…Ruxolitinib treatment reduced Akt and mTOR phosphorylation ( Figure 7E-F). Recently, yes-associated protein (Yap) was shown as a downstream of mTOR and involved in UUO kidney [12,20]. Indeed, Ruxolitinib treatment inhibited Yap expression ( Figure 7E-F).…”

Section: Ruxolitinib Attenuates Akt/mtor/yap Pathwaymentioning

confidence: 91%

“…Moreover, Erk and Akt signaling pathways were revealed to have a pro-proliferative effect on myofibroblasts by affecting molecules involved in cell cycle such as c-Myc, cyclin D1 and p21 [7,8]. Recently, the mammalian target of rapamycin (mTOR) was found implicated in fibroblast proliferation and activation [9,10,11,12]. Activation of Stat3 signaling may be another mechanism underlying renal interstitial fibrosis.…”

Section: Introductionmentioning

confidence: 99%

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Ruxolitinib Alleviates Renal Interstitial Fibrosis in UUO Mice

et al. 2020

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Ruxolitinib is a selective inhibitor of Jak1/2. Downstream signaling pathways of Jak, such as Stat3 and Akt/mTOR, are overactivated and contribute to renal interstitial fibrosis. Therefore, we explored the effect of Ruxolitinib on this pathological process. Unilateral ureteral obstruction (UUO) models and TGF-β1-treated fibroblasts and renal tubular epithelial cells were adopted in this study. Ruxolitinib was administered to UUO mice and TGF-β1-treated cells. Kidneys from UUO mice with Ruxolitinib treatment displayed less tubular injuries compared with those without Ruxolitinib treatment. Ruxolitinib treatment suppressed fibroblast activation and extracellular matrix (ECM) production in UUO kidneys and TGF-β1-treated fibroblasts. Ruxolitinib treatment also blocked epithelial-mesenchymal transition (EMT) in UUO kidneys and TGF-β 1-treated renal tubular epithelial cells. Moreover, Ruxolitinib treatment alleviated UUO-induced inflammation, oxidative stress and apoptosis. Mechanistically, Ruxolitinib treatment attenuated activation of both Stat3 and Akt/mTOR/Yap pathways. In conclusion, Ruxolitinib treatment can ameliorate UUO-induced renal interstitial fibrosis, suggesting that Ruxolitinib may be potentially used to treat fibrotic kidney disease.

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Section: Discussionmentioning

confidence: 99%

Section: Ruxolitinib Attenuates Akt/mtor/yap Pathwaymentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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Ruxolitinib Alleviates Renal Interstitial Fibrosis in UUO Mice

et al. 2020

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“…scaffold protein for mTORC2 that can phosphorylate Akt, protein kinase C (PKC), and serum-and glucocorticoidinduced kinases 1 (SGK1) 14,15 , and Rictor-deficient mice showed a remarkably decreased mTORC2 activity 16 . Our previous studies revealed that endogenous Rictor protects against renal inflammation and cisplatin-induced AKI, moreover, Rictor/mTORC2 stimulates Yap/Taz transcription 17,18 . Thus, we predicted that Rictor/mTORC2 may protect against renal inflammation and acute kidney injury via the Yap/Taz-NF-κB axis.…”

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confidence: 96%

Loss of Rictor in tubular cells exaggerates lipopolysaccharide induced renal inflammation and acute kidney injury via Yap/Taz-NF-κB axis

Gui

Hou

et al. 2020

Cell Death Discov.

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Our previous study demonstrated that the mammalian target of rapamycin complex 2 (mTORC2) signaling alleviates renal inflammation and protects against cisplatin-induced AKI. However, the underlying mechanisms for mTORC2 in regulating renal inflammation in AKI remain to be determined. In this study, we found that lipopolysaccharide (LPS) could activate mTORC2 signaling in NRK-52E cells, and blockage of mTORC2 signaling led to Yap/Taz degradation, which in turn activated NF-κB signaling and induced inflammatory cytokines secretion. Overexpression of constitutively active Taz (Taz-S89A) could attenuate the inflammation-amplified role of mTORC2 blockage. In mouse models, tubule-specific deletion of Rictor had higher blood urea nitrogen level, severe morphological injury as well as more inflammatory cells accumulation compared with those in their littermate controls. Overall, these results demonstrate that mTORC2 signaling protects against renal inflammation and dictates the outcome of AKI by modulating Yap/Taz degradation. Introduction Acute kidney injury (AKI) is an extremely lifethreatening clinical syndrome characterized by a rapid decrease in renal function. Tubulointerstitial inflammatory cells infiltration is the main characteristic of AKI. Accumulated evidence unveils that tubular cells play important roles in AKI-related inflammation. Tubular cells are always the initial site of injury caused by hypoxia or ischemia, which in turn secretes inflammatory mediators and recruits inflammatory cells infiltration, exacerbating renal injury 1-4. However, the mechanisms by which tubular cells trigger kidney inflammation remain unclear. The evolutionarily conserved Hippo signaling pathway is recognized as a regulator of cell proliferation, organ size, and tissue regeneration. MST1/2, SAV1, LATS1/2, MOB1A/B, Yes-associated protein (YAP) and its paralogue TAZ (also known as WWTR1) consist of the core components of the Hippo pathway. Among them, YAP and TAZ are the key downstream effectors of the Hippo pathway via MST1 and LATS kinases phosphorylation 5-8. Recently, several studies have uncovered the roles of Yap/ Taz in regulating inflammatory and immune responses 9,10. Deng et al. reported that phosphorylated Yap is sufficient to attenuate inflammatory responses in osteoarthritis by suppressing NF-κB signaling 10. However, the mechanisms by which NF-κB signaling triggers Yap/ Taz inhibiting inflammatory response are not fully clarified. The mammalian target of rapamycin (mTOR) plays an essential role in regulating cell growth, proliferation, and survival. The serine/threonine kinase mTOR consist of two distinct complexes: mTOR complex 1 (mTORC1) and complex 2 (mTORC2) 11-13. Rictor is a critical adapter

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“…Activation of mTORC1 signaling in fibroblasts promotes renal interstitial fibrosis. Ablation of Rictor in fibroblasts attenuates UUO nephropathy in mice[7,8,50]. In macrophages, mTORC2 signaling activation is indispensable for macrophage M2 polarization and UUO or IRI-induced kidney fibrosis[51]…”

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confidence: 99%

mTOR Signaling in Kidney Diseases

Gui

Dai

2020

Kidney360

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The mammalian target of rapamycin (mTOR), a serine/threonine protein kinase, is crucial in regulating cell growth, metabolism, proliferation and survival. Under physiologic condition, mTOR signaling maintains podocyte and tubular cell homeostasis. In acute kidney injury, activation of mTOR signaling in tubular cells and interstitial fibroblasts promotes renal regeneration and repair. However, constitutive activation of mTOR signaling in kidneys results in the initiation and progression of glomerular hypertrophy, interstitial fibrosis, polycystic kidney disease and renal cell carcinoma. Here, we summarize the recent studies about mTOR signaling in renal physiology and injury and discuss the possibility of which as a therapeutic target for kidney diseases.

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Yap/Taz mediates mTORC2-stimulated fibroblast activation and kidney fibrosis

Cited by 43 publications

References 47 publications

Ruxolitinib Alleviates Renal Interstitial Fibrosis in UUO Mice

Ruxolitinib Alleviates Renal Interstitial Fibrosis in UUO Mice

Loss of Rictor in tubular cells exaggerates lipopolysaccharide induced renal inflammation and acute kidney injury via Yap/Taz-NF-κB axis

mTOR Signaling in Kidney Diseases

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