Inhibition of <scp>EZH2</scp> suppresses peritoneal angiogenesis by targeting a <scp>VEGFR2</scp>/<scp>ERK1</scp>/2/<scp>HIF</scp>‐1α‐dependent signaling pathway

Shi, Yingfeng; Li, Jinqing; Chen, Hui; Hu, Yan; Tang, Lunxian; Wang, Yi; Zang, Xiao; Ma, Xiaoyan; Huang, Guansen; Zhou, Xun; Tao, Min; Lv, Zexin; Chen, Si; Qiu, Andong; Zhuang, Songlin; Liu, Na

doi:10.1002/path.5987

Cited by 10 publications

(8 citation statements)

References 62 publications

(79 reference statements)

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“…All the dialysate was glucose‐based PD fluid from Dianeal Baxter company. Exclusion criteria were diagnosis of peritonitis within the past 6 months, active autoimmune diseases, active inflammatory processes, and malignant tumors 21,22 . Overnight dialysate samples were obtained, and peritoneal equilibration tests (PET) were performed in the PD center of Shanghai Changhai Hospital.…”

Section: Methodsmentioning

confidence: 99%

“…Exclusion criteria were diagnosis of peritonitis within the past 6 months, active autoimmune diseases, active inflammatory processes, and malignant tumors. 21,22 Overnight dialysate samples were obtained, and peritoneal equilibration tests (PET) were performed in the PD center of Shanghai Changhai Hospital. The clinical characteristics of recruited patients are shown in Table 1.…”

Section: Clinical Peritoneal Dialysate Collectionmentioning

confidence: 99%

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SPHK1/S1P/S1PR pathway promotes the progression of peritoneal fibrosis by mesothelial‐mesenchymal transition

Zhao,

Ding,

Sun

et al. 2024

The FASEB Journal

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Long‐term exposure to non‐physiologically compatible dialysate inevitably leads to peritoneal fibrosis (PF) in patients undergoing peritoneal dialysis (PD), and there is no effective prevention or treatment for PF. Sphingosine‐1‐phosphate (S1P) is a bioactive sphingolipid produced after catalysis by sphingosine kinase (SPHK) 1/2 and activates signals through the S1P receptor (S1PR) via autocrine or paracrine. However, the role of SPHK1/S1P/S1PR signaling has never been elucidated in PF. In our research, we investigated S1P levels in peritoneal effluents and demonstrated the role of SPHK1/S1P/S1PR pathway in peritoneal fibrosis. It was found that S1P levels in peritoneal effluents were positively correlated with D/P Cr (r = 0.724, p < .001) and negatively correlated with 4 h ultrafiltration volume (r = −0.457, p < .001). S1PR1 and S1PR3 on peritoneal cells were increased after high glucose exposure in vivo and in vitro. Fingolimod was applied to suppress S1P/S1PR pathway. Fingolimod restored mouse peritoneal function by reducing interstitial hyperplasia, maintaining ultrafiltration volume, reducing peritoneal transport solute rate, and mitigating the protein expression changes of fibronectin, vimentin, α‐SMA, and E‐cadherin induced by PD and S1P. Fingolimod preserved the morphology of the human peritoneal mesothelial cells, MeT‐5A, and moderated the mesothelial‐mesenchymal transition (MMT) process. We further delineated that SPHK1 was elevated in peritoneal cells after high glucose exposure and suppression of SPHK1 in MeT‐5A cells reduced S1P release. Overexpression of SPHK1 in MeT‐5A cells increased S1P levels in the supernatant and fostered the MMT process. PF‐543 treatment, targeting SPHK1, alleviated deterioration of mouse peritoneal function. In conclusion, S1P levels in peritoneal effluent were correlated with the deterioration of peritoneal function. SPHK1/S1P/S1PR pathway played an important role in PF.

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Section: Methodsmentioning

confidence: 99%

Section: Clinical Peritoneal Dialysate Collectionmentioning

confidence: 99%

SPHK1/S1P/S1PR pathway promotes the progression of peritoneal fibrosis by mesothelial‐mesenchymal transition

Zhao,

Ding,

Sun

et al. 2024

The FASEB Journal

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“…Studies from our group have demonstrated that the activation of EGFR/ERK/1/2/STAT3 signaling pathway is related to the progression of peritoneal fibrosis (21,22). Therefore, we investigated the effect of HDAC8 on the activation of EGFR and its downstream signaling molecules ERK1/2 and STAT3.…”

Section: Inhibition Of Hdac8 Suppresses Development Of Peritoneal Fib...mentioning

confidence: 99%

Histone deacetylase 8 inhibition prevents the progression of peritoneal fibrosis by counteracting the epithelial-mesenchymal transition and blockade of M2 macrophage polarization

et al. 2023

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BackgroundPeritoneal dialysis (PD) is an effective replacement therapy for end-stage renal disease patients. However, long-term exposure to peritoneal dialysate will lead to the development of peritoneal fibrosis. Epigenetics has been shown to play an important role in peritoneal fibrosis, but the role of histone deacetylases 8 (HDAC8) in peritoneal fibrosis have not been elucidated. In this research, we focused on the role and mechanisms of HDAC8 in peritoneal fibrosis and discussed the mechanisms involved.MethodsWe examined the expression of HDAC8 in the peritoneum and dialysis effluent of continuous PD patients. Then we assessed the role and mechanism of HDAC8 in peritoneal fibrosis progression in mouse model of peritoneal fibrosis induced by high glucose peritoneal dialysis fluid by using PCI-34051. In vitro, TGF-β1 or IL-4 were used to stimulate human peritoneal mesothelial cells (HPMCs) or RAW264.7 cells to establish two cell injury models to further explore the role and mechanism of HDAC8 in epithelial-mesenchymal transition (EMT) and macrophage polarization.ResultsWe found that HDAC8 expressed highly in the peritoneum from patients with PD-related peritonitis. We further revealed that the level of HDAC8 in the dialysate increased over time, and HDAC8 was positively correlated with TGF-β1 and vascular endothelial growth factor (VEGF), and negatively correlated with cancer antigen 125. In mouse model of peritoneal fibrosis induced by high glucose dialysate, administration of PCI-34051 (a selective HDAC8 inhibitor) significantly prevented the progression of peritoneal fibrosis. Treatment with PCI-34051 blocked the phosphorylation of epidermal growth factor receptor (EGFR) and the activation of its downstream signaling pathways ERK1/2 and STAT3/HIF-1α. Inhibition of HDAC8 also reduced apoptosis. In vitro, HDAC8 silencing with PCI-34051 or siRNA inhibited TGF-β1-induced EMT and apoptosis in HPMCs. In addition, continuous high glucose dialysate or IL-4 stimulation induced M2 macrophage polarization. Blockade of HDAC8 reduced M2 macrophage polarization by inhibiting the activation of STAT6 and PI3K/Akt signaling pathways. ConclusionsWe demonstrated that HDAC8 promoted the EMT of HPMCs via EGFR/ERK1/2/STAT3/HIF-1α, induced M2 macrophage polarization via STAT6 and PI3K/Akt signaling pathways, and ultimately accelerated the process of peritoneal fibrosis.

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“…Histone methylation has also been implicated in PF, as Maeda et al demonstrated that the expression of H3K9 histone methyltransferase and H3K4 methyltransferase can exacerbate the thickening of the submesothelial compact zone ( Maeda et al, 2017 ). Recent studies have also linked high expression of EZH2 (Zeste homologue enhancer 2) with peritoneal fibrosis, possibly through the activation of profibrotic signalling pathways ( Wang et al, 2020 ; Shi et al, 2022 ).…”

Section: Regulation Of Epigenetic Genesmentioning

confidence: 99%

A review of research progress on mechanisms of peritoneal fibrosis related to peritoneal dialysis

Li,

Liu,

Liu

2023

Front. Physiol.

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Peritoneal dialysis (PD) is an effective alternative treatment for patients with end-stage renal disease (ESRD) and is increasingly being adopted and promoted worldwide. However, as the duration of peritoneal dialysis extends, it can expose problems with dialysis inadequacy and ultrafiltration failure. The exact mechanism and aetiology of ultrafiltration failure have been of great concern, with triggers such as biological incompatibility of peritoneal dialysis solutions, uraemia toxins, and recurrent intraperitoneal inflammation initiating multiple pathways that regulate the release of various cytokines, promote the transcription of fibrosis-related genes, and deposit extracellular matrix. As a result, peritoneal fibrosis occurs. Exploring the pathogenic factors and molecular mechanisms can help us prevent peritoneal fibrosis and prolong the duration of Peritoneal dialysis.

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Inhibition of EZH2 suppresses peritoneal angiogenesis by targeting a VEGFR2/ERK1/2/HIF‐1α‐dependent signaling pathway

Cited by 10 publications

References 62 publications

SPHK1/S1P/S1PR pathway promotes the progression of peritoneal fibrosis by mesothelial‐mesenchymal transition

SPHK1/S1P/S1PR pathway promotes the progression of peritoneal fibrosis by mesothelial‐mesenchymal transition

Histone deacetylase 8 inhibition prevents the progression of peritoneal fibrosis by counteracting the epithelial-mesenchymal transition and blockade of M2 macrophage polarization

A review of research progress on mechanisms of peritoneal fibrosis related to peritoneal dialysis

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