Effects of Arkadia on airway remodeling through enhancing TGF-β signaling in allergic rats

Li, Xiaozhao; Feng, Juntao; Chen, Ze‐Qi; Gu, Qing; Nie, Hua-Ping

doi:10.1038/labinvest.2010.78

Cited by 9 publications

(3 citation statements)

References 28 publications

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“…Ski expression has been shown to inhibit vascular smooth muscle cell proliferation by suppressing Tgfb/Smad3 signaling but up-regulating p38 signaling [Li et al, 2013]. Activation of Tgfb signaling in OVA-sensitized and -challenged rats has been found to contribute to the pathogenesis of airway remodeling through the reduction of Ski proteins [Li et al, 2010]. We found CpG site-specific hypomethylation at Tgfβ2, Smad2 and Smad3 , and Ski hypermethylation in lung and MASMCs, which may be associated with HDM-induced AHR.…”

Section: Discussionmentioning

confidence: 99%

Alterations of the lung methylome in allergic airway hyper‐responsiveness

Cheng

Shang

Limjunyawong

et al. 2014

Environ and Mol Mutagen

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Asthma is a chronic airway disorder characterized by recurrent attacks of breathlessness and wheezing, affecting 300 million people around the world (available at: www.who.int). To date, genetic factors associated with asthma susceptibility have been unable to explain the full etiology of asthma. Recent studies have demonstrated that the epigenetic disruption of gene expression plays an equally important role in the development of asthma through interaction with our environment. We sensitized 6-week-old C57BL/6J mice with house-dust-mite (HDM) extracts intraperitoneally followed by 5 weeks of exposure to HDM challenges (three times a week) intratracheally. HDM-exposed mice showed an increase in airway hyper-responsiveness (AHR) and inflammation together with structural remodeling of the airways. We applied methylated DNA immunoprecipitation-next generation sequencing (MeDIP-seq) for profiling of DNA methylation changes in the lungs in response to HDM. We observed about 20 million reads by a single-run of massive parallel sequencing. We performed bioinformatics and pathway analysis on the raw sequencing data to identify differentially methylated candidate genes in HDM-exposed mice. Specifically, we have revealed that the transforming growth factor beta signaling pathway is epigenetically modulated by chronic exposure to HDM. Here, we demonstrated that a specific allergen may play a role in AHR through an epigenetic mechanism by disrupting the expression of genes in lungs that might be involved in airway inflammation and remodeling. Our findings provide new insights into the potential mechanisms by which environmental allergens induce allergic asthma and such insights may assist in the development of novel preventive and therapeutic options for this debilitative disease.

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Section: Discussionmentioning

confidence: 99%

Alterations of the lung methylome in allergic airway hyper‐responsiveness

Cheng

Shang

Limjunyawong

et al. 2014

Environ and Mol Mutagen

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“…In addition, miR-142-3p can modulate ASMC phenotypes via a TGF-β-mediated mechanism [12]. One study suggested a close correlation between the activation of the TGF-β pathway and the pathogenesis underlying asthma-induced airway remodeling [13]. Epidermal growth factor receptor (EGFR) activation plays an essential role in the migration, differentiation and proliferation of numerous human epithelial cell types [14].…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-142 Inhibits Proliferation and Promotes Apoptosis in Airway Smooth Muscle Cells During Airway Remodeling in Asthmatic Rats via the Inhibition of TGF-β -Dependent EGFR Signaling Pathway

Wang¹,

Wang²,

Su³

2018

Cell Physiol Biochem

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Background/Aims: Asthma is a heterogeneous disease characterized by chronic airway inflammation resulting from airway hyper-responsiveness to diverse stimuli. In this study, we investigated whether microRNA-142 (miR-142) expression affects proliferation and apoptosis in airway smooth muscle cells (ASMCs) during airway remodeling in asthmatic rats. Methods: Thirty six Wistar rats were randomly classified into a control group and an model group. miR-142 mimics and inhibitors were constructed, and ASMCs were transfected using liposomes according to the following groups: blank, negative control (NC), miR-142 mimics, miR-142 inhibitors, si-TGF-β and miR-142 inhibitors + si-TGF-β. We verified that miR-142 targets TGF-β using a dual-luciferase reporter assay. The expression levels of miR-142, TGF-β, EGFR and apoptosis signaling pathway-related genes were determined using RT-qPCR and western blotting. Changes in cell proliferation, cell cycle progression and apoptosis were analyzed using MTT assays and flow cytometry. Results: Rats with asthma had higher expression levels of EGFR and Akt and lower miR-142 levels. miR-142 was negatively correlated with TGF-β expression. In ASMCs, the expression of TGF-β, EGFR, Akt, phosphorylated-Akt (p-Akt), Bcl-2 and Bcl-xl and the rate of early apoptosis were decreased while expression of Bax and p21 and the proliferation rate were elevated with the upregulation of miR-142. The opposite results were observed with the downregulation of miR-142. Finally, the proliferative rate was decreased while the apoptosis rate was increased and expression levels of EGFR, Akt, p-Akt, Bcl-2 and Bcl-xl were reduced while Bax and p21 were elevated in the ASMCs transfected with miR-142 inhibitors and si-TGF-β. Conclusion: The results of our study suggest that miR-142 inhibits proliferation and promotes apoptosis in ASMCs during airway remodeling in asthmatic rats by inhibiting TGF-β expression via a mechanism involving the EGFR signaling pathway.

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“…As aforementioned, Smurf2 and Arkadia were highly expressed in the renal tissues of DN rats in the present study. TGF-β enhances its biological effects by modulating the Arkadia-mediated SnoN degradation (29,30). Arkadia binds the SnoN protein with the carboxy-terminal RING domain (28) and induces ubiquitin-mediated degradation of the SnoN protein in the presence of p-Smad2/3 involvement (31).…”

Section: Discussionmentioning

confidence: 99%

Blood glucose control contributes to protein stability of Ski‑related novel protein N in a rat model of diabetes

Liang

Liu

et al. 2021

Exp Ther Med

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Ski-related novel protein N (SnoN) negatively regulates the transforming growth factor-β1 (TGF-β1)/Smads signaling pathway and is present at a low level during diabetic nephropathy (DN), but its underlying regulatory mechanism is currently unknown. The present study aimed to assess the effects of insulin-controlled blood glucose on renal SnoN expression and fibrosis in rats with diabetes mellitus (DM). Streptozotocin-induced DM rats were treated with insulin glargine (INS group) following successful model establishment. Blood samples were collected and centrifuged for biochemical indexes and the kidneys were collected for morphological analysis. In vitro, rat renal proximal tubular epithelial cells were treated with high-glucose medium for 24 h and transferred to normal glucose medium for 24 h. The expression levels of TGF-β1, SnoN, Smad ubiquitin regulatory factor 2 (Smurf2), Arkadia, Smads, E-cadherin, α-smooth muscle actin and collagen III were assessed by western blotting and immunohistochemistry. The ubiquitylation of SnoN was detected by immunoprecipitation, and the expression levels of SnoN mRNA were evaluated by reverse transcription-quantitative PCR. The biochemical parameters and morphology indicated that renal fibrosis was notable in the DM group and mitigated in the INS group. Compared with the control group, TGF-β1, phosphor (p)-Smad2, p-Smad3, Smurf2 and Arkadia levels were enhanced in the DM group, and the levels of SnoN protein were decreased, whereas the levels of SnoN mRNA and ubiquitylation were increased in renal tissues. Notably, treatment with insulin reversed this trend. Furthermore, changing the glucose levels in the medium from high to normal glucose suppressed the epithelial-mesenchymal transition of NRK-52E cells by restoring the SnoN protein levels, and this phenomenon was impaired by the knockout of SnoN. SnoN protein levels were likely reduced through a mechanism enhanced by the ubiquitin proteasome system, which reversed the transcriptional activation of SnoN during DN progression. In addition, controlling blood glucose may delay DN fibrosis by rescuing the protein stability of SnoN.

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Effects of Arkadia on airway remodeling through enhancing TGF-β signaling in allergic rats

Cited by 9 publications

References 28 publications

Alterations of the lung methylome in allergic airway hyper‐responsiveness

Alterations of the lung methylome in allergic airway hyper‐responsiveness

MicroRNA-142 Inhibits Proliferation and Promotes Apoptosis in Airway Smooth Muscle Cells During Airway Remodeling in Asthmatic Rats via the Inhibition of TGF-β -Dependent EGFR Signaling Pathway

Blood glucose control contributes to protein stability of Ski‑related novel protein N in a rat model of diabetes

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