Beta‐catenin participates in dialysate‐induced peritoneal fibrosis <i>via</i> enhanced peritoneal cell epithelial‐to‐mesenchymal transition

Ji, Shuiyu; Deng, Hao; Jin, Wei; Yan, Pengpeng; Wang, Rending; Pang, Lisha; Zhou, Jingyi; Zhang, Jiaming; Chen, Xiaoying; Zhao, Xiaojun; Shen, Jia

doi:10.1002/2211-5463.12182

Cited by 18 publications

(19 citation statements)

References 22 publications

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“…We used Dickkopf‐related protein (DKK‐1) to inhibit WNT/β‐catenin signalling and observed a decrease in both angiogenesis and also epithelial to mesenchymal transition (EMT) . In a similar study of dialysis infused peritoneal fibrosis, β‐catenin was shown to induce EMT . Our results concur with reports of WNT signalling in other fibrotic diseases …”

Section: Introductionsupporting

confidence: 92%

The role of WNT5A and Ror2 in peritoneal membrane injury

Padwal

Liu

Margetts

2020

J Cellular Molecular Medi

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Patients on peritoneal dialysis are at risk of developing peritoneal fibrosis and angiogenesis, which can lead to dysfunction of the peritoneal membrane. Recent evidence has identified cross‐talk between transforming growth factor beta (TGFB) and the WNT/β‐catenin pathway to induce fibrosis and angiogenesis. Limited evidence exists describing the role of non‐canonical WNT signalling in peritoneal membrane injury. Non‐canonical WNT5A is suggested to have different effects depending on the receptor environment. WNT5A has been implicated in antagonizing canonical WNT/β‐catenin signalling in the presence of receptor tyrosine kinase‐like orphan receptor (Ror2). We co‐expressed TGFB and WNT5A using adenovirus and examined its role in the development of peritoneal fibrosis and angiogenesis. Treatment of mouse peritoneum with AdWNT5A decreased the submesothelial thickening and angiogenesis induced by AdTGFB. WNT5A appeared to block WNT/β‐catenin signalling by inhibiting phosphorylation of glycogen synthase kinase 3 beta (GSK3B) and reducing levels of total β‐catenin and target proteins. To examine the function of Ror2, we silenced Ror2 in a human mesothelial cell line. We treated cells with AdWNT5A and observed a significant increase in fibronectin compared with AdWNT5A alone. We also analysed fibronectin and vascular endothelial growth factor (VEGF) in a TGFB model of mesothelial cell injury. Both fibronectin and VEGF were significantly increased in response to Ror2 silencing when cells were exposed to TGFB. Our results suggest that WNT5A inhibits peritoneal injury and this is associated with a decrease in WNT/β‐catenin signalling. In human mesothelial cells, Ror2 is involved in regulating levels of fibronectin and VEGF.

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Section: Introductionsupporting

confidence: 92%

The role of WNT5A and Ror2 in peritoneal membrane injury

Padwal

Liu

Margetts

2020

J Cellular Molecular Medi

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“…Furthermore, Ppar-γ, a nuclear receptor which is associated with PSC quiescence [4,22,25,26], is known to have anti-inflammatory/anti-fibrotic activity [36] and should compete with β-catenin for binding to CBP's N-terminal region, thereby phenocopying ICG-001 antagonism of CBP/β-catenin binding and associated signaling [37]. As such, it is not surprising that various studies have shown that treatment with CBP/β-catenin antagonist ICG-001 (or the structurally related derivative PRI-724) is effective pre-clinically at ameliorating fibrosis in the peritoneum [38], endometrium [39], lung [13], kidney [32], skin [40], heart [41], and liver [19,42]. Importantly, a recent phase 1 trial utilizing PRI-724 demonstrated that treatment of patients safely improved liver histology and Child-Pugh scores for cirrhosis [43], suggesting that CBP/β-catenin antagonism is a viable therapeutic for combating fibrotic diseases in general.…”

Section: Discussionmentioning

confidence: 99%

Targeting the CBP/β-Catenin Interaction to Suppress Activation of Cancer-Promoting Pancreatic Stellate Cells

Che

Kweon

Teo

et al. 2020

Cancers

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Background: Although cyclic AMP-response element binding protein-binding protein (CBP)/β-catenin signaling is known to promote proliferation and fibrosis in various organ systems, its role in the activation of pancreatic stellate cells (PSCs), the key effector cells of desmoplasia in pancreatic cancer and fibrosis in chronic pancreatitis, is largely unknown. Methods: To investigate the role of the CBP/β-catenin signaling pathway in the activation of PSCs, we have treated mouse and human PSCs with the small molecule specific CBP/β-catenin antagonist ICG-001 and examined the effects of treatment on parameters of activation. Results: We report for the first time that CBP/β-catenin antagonism suppresses activation of PSCs as evidenced by their decreased proliferation, down-regulation of “activation” markers, e.g., α-smooth muscle actin (α-SMA/Acta2), collagen type I alpha 1 (Col1a1), Prolyl 4-hydroxylase, and Survivin, up-regulation of peroxisome proliferator activated receptor gamma (Ppar-γ) which is associated with quiescence, and reduced migration; additionally, CBP/β-catenin antagonism also suppresses PSC-induced migration of cancer cells. Conclusion: CBP/β-catenin antagonism represents a novel therapeutic strategy for suppressing PSC activation and may be effective at countering PSC promotion of pancreatic cancer.

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“…Although TGF-β1 and/or the renin-angiotensin system are the classical mediators of peritoneal fibrosis, recent reports have revealed the significance of other signaling pathways in peritoneal fibrosis [24–28]. Ji et al [25] investigated the role of β-catenin, a cytoskeletal protein, in high-glucose dialysate-induced EMT pathology. They found that inhibiting β-catenin reversed the expression of high-glucose-induced EMT markers.…”

Section: Discussionmentioning

confidence: 99%

Effects of tranilast on the epithelial-to-mesenchymal transition in peritoneal mesothelial cells

Kang

Kim

et al. 2019

Kidney Res Clin Pract

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BackgroundWe investigated the effects of tranilast on epithelial-to-mesenchymal transition (EMT) in an animal model and on the EMT signaling pathway in human peritoneal mesothelial cells (HPMCs).MethodsWe performed in vitro studies (cytotoxicity, cell morphology, and western blot analyses) on HPMCs from human omenta, along with in vivo studies (peritoneal membrane function and morphometric and immunohistochemical analyses) on Sprague Dawley rats. Thirty-two rats were divided into three groups: control (C) group (peritoneal dialysis [PD] catheter but not infused with dialysate), PD group (4.25% glucose-containing dialysate), and PD + tranilast group (4.25% glucose-containing dialysate along with tranilast).ResultsIn in vitro experiments, transforming growth factor-beta 1 (TGF-β1) increased α-smooth muscle actin and Snail expression and reduced E-cadherin expression in HPMCs. TGF-β1 also reduced cell contact, induced a fibroblastoid morphology, and increased phosphorylation of Akt, Smad2, and Smad3 in HPMCs. Tranilast significantly inhibited TGF-β1-induced EMT and attenuated these morphological changes in HPMCs. In in vivo studies, after 6 weeks of experimental PD, the peritoneal membrane was significantly thicker in the PD group than in the C group. Tranilast protected against PD-induced glucose mass transfer change and histopathological changes in rats.ConclusionTranilast prevented EMT both in HPMCs triggered with TGF-β1 and in rats with PD-induced peritoneal fibrosis. Thus, tranilast may be considered a therapeutic intervention that enables long-term PD by regulating TGF-β1 signaling pathways.

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Beta‐catenin participates in dialysate‐induced peritoneal fibrosis via enhanced peritoneal cell epithelial‐to‐mesenchymal transition

Cited by 18 publications

References 22 publications

The role of WNT5A and Ror2 in peritoneal membrane injury

The role of WNT5A and Ror2 in peritoneal membrane injury

Targeting the CBP/β-Catenin Interaction to Suppress Activation of Cancer-Promoting Pancreatic Stellate Cells

Effects of tranilast on the epithelial-to-mesenchymal transition in peritoneal mesothelial cells

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