Inhibiting core fucosylation attenuates glucose-induced peritoneal fibrosis in rats

Li, Longkai; Shen, Nan; Wang, Nan; Wang, Weidong; Tang, Qingzhu; Du, Xiangning; Carrero, Juan Jesús; Keping, Wang; Deng, Yiyao; Li, Zhitong; Lin, Hongli; Wu, Ting

doi:10.1016/j.kint.2017.12.023

Cited by 26 publications

(29 citation statements)

References 54 publications

(82 reference statements)

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“…Since Fut8 is the unique fucosyltransferase responsible for core fucosylation, three Fut8 short hairpin RNAs (Fut8shRNA) were chemically synthesized and connected [ 14 ]. Then, a Fut8-knockdown rat model with peritoneal fibrosis was created, which has been described previously in more detail [ 17 ]. The recombinant adenovirus-control was also constructed following the same procedure [ 14 ].…”

Section: Methodsmentioning

confidence: 99%

“…Currently, posttranslational modifications of proteins mediate direct and definitive regulation of their functions and affect the activation of multiple signaling pathways [ 14 , 15 ], where TGF-β1, PDGF, and EGF pathway receptors are modified by core fucosylation that is catalyzed by α1,6-fucosyltransferase (Fut8) [ 16 ]. Our previous studies showed that inhibiting core fucosylation of TGF-β1 and PDGF receptors significantly ameliorated the progression of peritoneal fibrosis in rats [ 17 ]. However, other glycoproteins, such as the EGF receptor, are also modified by core fucosylation.…”

Section: Introductionmentioning

confidence: 99%

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Blocking core fucosylation of epidermal growth factor (EGF) receptor prevents peritoneal fibrosis progression

Yang

Wang

et al. 2021

Renal Failure

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Objective Peritoneal fibrosis (PF) ultimately causes ultrafiltration failure and peritoneal dialysis (PD) termination, but there are few effective therapies for it. Core fucosylation, which is catalyzed by α1,6-fucosyltransferase (Fut8) in mammals, may play a crucial role in PF development. This study aims to assess the effects of inhibiting core fucosylation of epidermal growth factor (EGF) receptor on PF rats. Methods PF rats (established by 4.25% glucose dialysate) were treated with either an adenovirus-Fut8 short hairpin RNA (Fut8shRNA) or adenovirus-control. Masson’s staining and net ultrafiltration were performed at week six. Fut8 level and core fucosylation of EGF receptor and collagen I in the peritoneal membrane were assessed, and EGF signaling was detected, including signal transducer and activator of transcription 3 (STAT3), nuclear factor kappa B (NF-κB) and their phosphorylation. Monocyte chemoattractant protein-1 (MCP-1) in peritoneal effluent was examined. Results Fut8 was upregulated in PF rats but decreased after Fut8shRNA treatment. EGF and EGF receptor expression was upregulated in PF rats, while core fucosylation of EGF receptor decreased after Fut8shRNA treatment. Masson’s staining results showed an increase in peritoneal thickness in PF rats but a decrease after Fut8shRNA treatment. Fut8shRNA treatment increased net ultrafiltration, reduced the expression of collagen I and MCP-1 compared to PF rats. Fut8shRNA treatment suppressed phosphorylation of STAT3 and NF-κB in the peritoneal membrane of PF rats. Conclusions Fut8shRNA treatment ameliorated the fibrotic changes in PF rats. A potential mechanism may be that Fut8shRNA treatment inactivated EGF signaling pathway by suppressing the phosphorylation of STAT3 and NF-κB.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Blocking core fucosylation of epidermal growth factor (EGF) receptor prevents peritoneal fibrosis progression

Yang

Wang

et al. 2021

Renal Failure

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“…Despite these findings, the detailed mechanism underlying PF still remains largely unclear (8), with treatment methods for patients suffering from PF undergoing continuous ambulatory PD (CAPD) remaining largely ineffective. This being said, an urgent need for more effective methods in the management of patients who have PF complications is required (9).…”

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confidence: 99%

Long noncoding RNA AK089579 inhibits epithelial‐to‐mesenchymal transition of peritoneal mesothelial cells by competitively binding to microRNA‐296‐3p via DOK2 in peritoneal fibrosis

2019

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Peritoneal fibrosis (PF) represents a well‐recognized complication associated with continuous ambulatory peritoneal dialysis therapy, characterized by a reversible epithelial‐to‐mesenchymal transition (EMT) at the early stage. The aim of the current study was to investigate the effects linked with the long noncoding RNA (IncRNA) AK089579 on the EMT of peritoneal mesothelial cells (PMCs) as well as the associated regulatory mechanisms of AK089579 downstream of tyrosine kinase 2 (DOK2) and microRNA‐296‐3p (miR‐296‐3p). Enrichment analysis, gene intersection association analysis, and a gene‐gene intersection network were initially constructed to ascertain whether AK089579 regulated the expression of DOK2 through the mediation of miR‐296‐3p via the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in PF. After the PF mouse model had been constructed, the expression of the proteins associated with the JAK2/STAT3 signaling pathway and EMT and PMC migration and invasion were all determined accordingly. Based on the obtained results, AK089579 was determined to function as a competing endogenous RNA for miR‐296‐3p while acting to up‐regulate the expression of DOK2, which is a target gene of miR‐296‐3p. AK089579 was detected to confer an inhibitory effect on the activation of the JAK2/STAT3 signaling pathway, whereby the migration and invasion of PMCs among the mice models were suppressed. Meanwhile, up‐regulated miR‐296‐3p and down‐regulated DOK2 produced contrasting effects when compared with the aforementioned findings. Treatment with wpl0066, a JAK2/STAS3 signaling pathway inhibitor, was shown to reverse the effects exerted by up‐regulated miR‐296‐3p. Taken together, the central findings of the current study present evidence highlighting the capability of the IncRNA AK089579 to bind competitively to miR‐296‐3p and indirectly enhance the expression of DOK2, which in turn suppresses the activation of the JAK2/STAT3 signaling pathway, whereby the EMT, migration, and invasion of PMCs was inhibited in PF.—Zhang, X. W., Wang, L., Ding, H. Long noncoding RNA AK089579 inhibits epithelial‐to‐mesenchymal transition of peritoneal mesothelial cells by competitively binding to microRNA‐296‐3p via DOK2 in peritoneal fibrosis. FASEB J. 33, 5112–5125 (2019). http://www.fasebj.org

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“…Peritoneal fibrosis (PF) induced by continuous exposure to high dextrose concentrations in dialysate is the major contributor of ultrafiltration failure, for which there is no effective treatment. 3 Approximately 50% of all PD patients may eventually develop progressive fibrosis, leading to inadequate diffusive and convective clearance due to angiogenesis, and vascular degeneration. 4 Other factors also influence membrane failure, including the mechanical stress of the dwelling solution, catheter complications, leading to injury and chronic inflammation of the peritoneum.…”

Section: Introductionmentioning

confidence: 99%

Peritoneal fibrosis and epigenetic modulation

et al. 2020

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Peritoneal dialysis (PD) is an effective treatment for patients with end-stage renal disease. However, peritoneal fibrosis (PF) is a common complication that ultimately leads to ultrafiltration failure and discontinuation of PD after long-term PD therapy. There is currently no effective therapy to prevent or delay this pathologic process. Recent studies have reported epigenetic modifications involved in PF, and accumulating evidence suggests that epigenetic therapies may have the potential to prevent and treat PF clinically. The major epigenetic modifications in PF include DNA methylation, histone modification, and noncoding RNAs. The mechanisms of epigenetic regulation in PF are complex, predominantly involving modification of signaling molecules, transcriptional factors, and genes. This review will describe the mechanisms of epigenetic modulation in PF and discuss the possibility of targeting them to prevent and treat this complication.

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Inhibiting core fucosylation attenuates glucose-induced peritoneal fibrosis in rats

Cited by 26 publications

References 54 publications

Blocking core fucosylation of epidermal growth factor (EGF) receptor prevents peritoneal fibrosis progression

Blocking core fucosylation of epidermal growth factor (EGF) receptor prevents peritoneal fibrosis progression

Long noncoding RNA AK089579 inhibits epithelial‐to‐mesenchymal transition of peritoneal mesothelial cells by competitively binding to microRNA‐296‐3p via DOK2 in peritoneal fibrosis

Peritoneal fibrosis and epigenetic modulation

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