The MEK Inhibitor Trametinib Ameliorates Kidney Fibrosis by Suppressing ERK1/2 and mTORC1 Signaling

Andrikopoulos, Petros; Kieswich, Julius; Pacheco, Sabrina; Nadarajah, Luxme; Harwood, Steven; O'Riordan, Caroline E; Thiemermann, Christoph; Yaqoob, Muhammad

doi:10.1681/asn.2018020209

Cited by 61 publications

(70 citation statements)

References 65 publications

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“…Notably, ERK signalling is a prominent feature of tubular epithelial cell injury across a wide range of kidney diseases, with ERK activation in tubular cells correlating with renal dysfunction, interstitial fibrosis and tubular atrophy . Consistent with human studies, there is prominent ERK activation in tubular cells and interstitial fibroblasts in the unilateral ureteric obstruction (UUO) model which correlates with cell proliferation, and a recent study has shown that ERK inhibitor treatment suppressed both cell proliferation and renal fibrosis in the UUO model . Macrophages also play a significant role in the development of renal fibrosis in the UUO model, and activation of PAR2 in human macrophages can induce TNF production …”

supporting

confidence: 57%

“…10 Consistent with human studies, there is prominent ERK activation in tubular cells and interstitial fibroblasts in the unilateral ureteric obstruction (UUO) model which correlates with cell proliferation, 11,12 and a recent study has shown that ERK inhibitor treatment suppressed both cell proliferation and renal fibrosis in the UUO model. 13 Macrophages also play a significant role in the development of renal fibrosis in the UUO model, 14 and activation of PAR2 in human macrophages can induce TNF production. 15 This study aimed to define the role of PAR2 in tubular damage, tubulointerstitial inflammation and fibrosis.…”

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confidence: 99%

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Protease‐activated receptor 2 does not contribute to renal inflammation or fibrosis in the obstructed kidney

et al. 2019

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Aim Protease‐activated receptor 2 (PAR2) has been implicated in the development of renal inflammation and fibrosis. In particular, activation of PAR2 in cultured tubular epithelial cells induces extracellular signal‐regulated kinase signalling and secretion of fibronectin, C–C Motif Chemokine Ligand 2 (CCL2) and transforming growth factor‐β1 (TGF‐β1), suggesting a role in tubulointerstitial inflammation and fibrosis. We tested this hypothesis in unilateral ureteric obstruction (UUO) in which ongoing tubular epithelial cell damage drives tubulointerstitial inflammation and fibrosis. Methods Unilateral ureteric obstruction surgery was performed in groups (n = 9/10) of Par2−/− and wild type (WT) littermate mice which were killed 7 days later. Non‐experimental mice were controls. Results Wild type mice exhibited a 5‐fold increase in Par2 messenger RNA (mRNA) levels in the UUO kidney. In situ hybridization localized Par2 mRNA expression to tubular epithelial cells in normal kidney, with a marked increase in Par2 mRNA expression by tubular cells, including damaged tubular cells, in WT UUO kidney. Tubular damage (tubular dilation, increased KIM‐1 and decreased α‐Klotho expression) and tubular signalling (extracellular signal‐regulated kinase phosphorylation) seen in WT UUO were not altered in Par2−/− UUO. In addition, macrophage infiltration, up‐regulation of M1 (NOS2) and M2 (CD206) macrophage markers, and up‐regulation of pro‐inflammatory molecules (tumour necrosis factor, CCL2, interleukin‐36α) in WT UUO kidney were unchanged in Par2−/− UUO. Finally, the accumulation of α‐SMA+ myofibroblasts, deposition of collagen IV and expression of pro‐fibrotic factors (CTGF, TGF‐β1) were not different between WT and Par2−/− UUO mice. Conclusion Protease‐activated receptor 2 expression is substantially up‐regulated in tubular epithelial cells in the obstructed kidney, but this does not contribute to the development of tubular damage, renal inflammation or fibrosis.

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confidence: 57%

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confidence: 99%

Protease‐activated receptor 2 does not contribute to renal inflammation or fibrosis in the obstructed kidney

et al. 2019

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“…Similarly, Ruxolitinib treatment inhibited Stat3 and Erk phosphorylation in TGF-β1 -treated NRK-49F cells ( Figure 7C-D). We further analyzed downstream molecules of Jak signaling such as Akt and mTOR which have been shown involved in obstructed kidney [9,10]. Consistent with these reports, UUO kidneys overexpressed Akt, p-Akt, mTOR and p-mTOR.…”

Section: Ruxolitinib Attenuates Akt/mtor/yap Pathwaysupporting

confidence: 71%

“…Our study finally identified that Ruxolitinib treatment attenuated Akt/mTOR pathway. 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].…”

Section: Discussionmentioning

confidence: 99%

“…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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Rictor/mTORC2 signalling contributes to renal vascular endothelial‐to‐mesenchymal transition and renal allograft interstitial fibrosis by regulating BNIP3‐mediated mitophagy

Feng,

Gui,

et al. 2024

Clinical & Translational Med

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BackgroundRenal allograft interstitial fibrosis/tubular atrophy (IF/TA) constitutes the principal histopathological characteristic of chronic allograft dysfunction (CAD) in kidney‐transplanted patients. While renal vascular endothelial‐mesenchymal transition (EndMT) has been verified as an important contributing factor to IF/TA in CAD patients, its underlying mechanisms remain obscure. Through single‐cell transcriptomic analysis, we identified Rictor as a potential pivotal mediator for EndMT. This investigation sought to elucidate the role of Rictor/mTORC2 signalling in the pathogenesis of renal allograft interstitial fibrosis and the associated mechanisms.MethodsThe influence of the Rictor/mTOR2 pathway on renal vascular EndMT and renal allograft fibrosis was investigated by cell experiments and Rictor depletion in renal allogeneic transplantation mice models. Subsequently, a series of assays were conducted to explore the underlying mechanisms of the enhanced mitophagy and the ameliorated EndMT resulting from Rictor knockout.ResultsOur findings revealed a significant activation of the Rictor/mTORC2 signalling in CAD patients and allogeneic kidney transplanted mice. The suppression of Rictor/mTORC2 signalling alleviated TNFα‐induced EndMT in HUVECs. Moreover, Rictor knockout in endothelial cells remarkably ameliorated renal vascular EndMT and allograft interstitial fibrosis in allogeneic kidney transplanted mice. Mechanistically, Rictor knockout resulted in an augmented BNIP3‐mediated mitophagy in endothelial cells. Furthermore, Rictor/mTORC2 facilitated the MARCH5‐mediated degradation of BNIP3 at the K130 site through K48‐linked ubiquitination, thereby regulating mitophagy activity. Subsequent experiments also demonstrated that BNIP3 knockdown nearly reversed the enhanced mitophagy and mitigated EndMT and allograft interstitial fibrosis induced by Rictor knockout.ConclusionsConsequently, our study underscores Rictor/mTORC2 signalling as a critical mediator of renal vascular EndMT and allograft interstitial fibrosis progression, exerting its impact through regulating BNIP3‐mediated mitophagy. This insight unveils a potential therapeutic target for mitigating renal allograft interstitial fibrosis.

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The MEK Inhibitor Trametinib Ameliorates Kidney Fibrosis by Suppressing ERK1/2 and mTORC1 Signaling

Cited by 61 publications

References 65 publications

Protease‐activated receptor 2 does not contribute to renal inflammation or fibrosis in the obstructed kidney

Protease‐activated receptor 2 does not contribute to renal inflammation or fibrosis in the obstructed kidney

Ruxolitinib Alleviates Renal Interstitial Fibrosis in UUO Mice

Rictor/mTORC2 signalling contributes to renal vascular endothelial‐to‐mesenchymal transition and renal allograft interstitial fibrosis by regulating BNIP3‐mediated mitophagy

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