miR-21 overexpression enhances TGF-β1-induced epithelial-to-mesenchymal transition by target smad7 and aggravates renal damage in diabetic nephropathy

Wang, Jinyang; Gao, Yanbin; Zhang, Na; Zou, Dawei; Wang, Peng; Zhu, Zhiyao; Li, Jiaoyang; Zhou, Shengnan; Wang, Shao-Cheng; Wang, Yingying; Yang, Jin-Kui

doi:10.1016/j.mce.2014.05.018

Cited by 138 publications

(109 citation statements)

References 40 publications

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“…They negatively regulate gene expression by inducing translational inhibition or transcript degradation [63]. miR-21 has recently been recognized as a biomarker in various types of diseases, and it has also been confirmed to mediate TGF-β signaling and EMT.…”

Section: Discussion/conclusionmentioning

confidence: 99%

TGF-β1 Induces Epithelial-Mesenchymal Transition of Chronic Sinusitis with Nasal Polyps through MicroRNA-21

Zhu

et al. 2019

Int Arch Allergy Immunol

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Objectives: To characterize the epithelial-mesenchymal transition (EMT) in chronic rhinosinusitis with nasal polyps (CRSwNP) and to investigate the mechanism by which microRNA-21 (miR-21) regulates EMT in CRSwNP. Method: (1) Tissue experiments: Mucosa tissues were collected from 13 patients with CRSwNP and 12 patients with CRS without nasal polyps (CRSsNP), as well as 11 patients without CRS (controls). Protein localization and quantification were achieved by immunofluorescence staining and Western blotting, involving the epithelial marker protein E-cadherin and the mesenchymal marker proteins α-smooth muscle actin (α-SMA), fibronectin, and vimentin. Quantitative RT-PCR was used to detect the relative expression levels of miR-21 and TGF-β1 mRNAs. (2) Cellular experiments: Primary human nasal epithelial cells (PHNECs) treated with TGF-β1, or TGF-β1 with miR-21 inhibitor, or miR-21 mimics alone were observed for morphology changes under a phase-contrast microscope. The expression levels of epithelial/mesenchymal marker proteins were determined as aforementioned. PTEN and phosphorylated Akt were detected by Western blotting. Results: (1) Tissue experiments: Compared with the CRSsNP and control groups, the expression of E-cadherin was downregulated in the CRSwNP group, whereas the expression of TGF-β1, α-SMA, fibronectin, and vimentin was upregulated. The expression levels of miR-21 and TGF-β1 mRNAs in CRSwNP were significantly higher than those in CRSsNP and controls. (2) Cellular experiments: TGF-β1 induced EMT-like transformation in PHNECs, featured by changes in cell morphology and upregulation of mesenchymal proteins and miR-21. The miR-21 inhibitor, as well as the Akt-specific inhibitor, suppressed TGF-β1-induced EMT. Mechanically, downregulation of miR-21 resulted in increased PTEN and decreased Akt phosphorylation. Furthermore, overexpression of miR-21 had the opposite effects. Conclusions: Our findings suggest that the TGF-β1-miR-21-PTEN-Akt axis may contribute to the pathogenesis of CRSwNP. miR-21 might be a reliable target for treating nasal polyp genesis through EMT suppression. Moreover, miR-21 inhibitors could be a novel class of antipolyp drug that modulates PTEN expression and Akt activation. In addition, further investigation regarding the reason underlying miR-21 overexpression in CRSwNP could provide a molecular target for novel treatment strategies for nasal polyposis.

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Section: Discussion/conclusionmentioning

confidence: 99%

TGF-β1 Induces Epithelial-Mesenchymal Transition of Chronic Sinusitis with Nasal Polyps through MicroRNA-21

Zhu

et al. 2019

Int Arch Allergy Immunol

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“…For example, TGF-β1 promotes the phosphorylation of R-smads by binding to the TGF-βR. In turn, the inhibitory smad7, a target of miR-21, can negatively regulate the phosphorylation of R-smads through the TGF-βR [40,41,42]. Whether TGF-β1 increases the Treg cell population and expression of foxp3 by a TGF-β1/smad-dependent signaling pathway or TGF-β1/smad-independent signaling pathways remains unknown [43,44,45].…”

Section: Expression Levels Of Mir-21 Foxp3 Tgf-β1 and Smad7 In Pbmcmentioning

confidence: 99%

MicroRNA-21 Negatively Regulates Treg Cells Through a TGF-β1/Smad-Independent Pathway in Patients with Coronary Heart Disease

Fan

et al. 2015

Cell Physiol Biochem

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Background: CD4+CD25+FoxP3+ regulatory T cells (Treg cells) play a protective role against the development and progression of the inflammatory disease atherosclerosis (AS). MicroRNA-21 (miR-21) is expressed in Treg cells and is up-regulated in the context of AS and other inflammatory diseases. Aims: This study aimed to determine the role of miR-21 in Treg cell regulation and gene expression during the development of AS in patients with coronary heart disease (CHD). Methods and Results: MiR-21 expression in peripheral blood mononuclear cells (PBMCs) was significantly up-regulated in patients with CHD (acute myocardial infarction (AMI) group, n=24; unstable angina (UA) group, n=21; stable angina (SA) group, n=24) compared with patients with chest pain syndrome (CPS, n=27), and miR-21 expression showed an increasing trend from SA to UA to AMI patients. Moreover, flow cytometry analysis indicated that the frequencies of circulating Treg cells decreased in a manner proportionate opposite with the level of miR-21. Quantitative real-time PCR (qRT-PCR) revealed a decrease in mRNA expression of forkhead box P3 (foxp3), transforming cell growth factor beta 1(TGF-β1) and smad7 (a known target gene of miR-21). ELISA analysis revealed a decrease in TGF-β1 secreted into the plasma. In addition, we transfected PBMCs with a miRNA negative control (NS-m), a miR-21 mimic (miR-21-m), a miRNA inhibitor negative control (NS-i), or a miR-21 inhibitor(miR-21-i). Up-regulation of miR-21 decreased the frequency of circulating Treg cells, decreased the expression levels of foxp3, TGF-β1 and smad7, and decreased the amount of TGF-β1 secreted into the plasma. Consistent with these observations, miR-21 down-regulation increased the frequency of circulating Treg cells, increased the expression of foxp3, TGF-β1 and smad7, and increased the amount of TGF-β1 secreted into the plasma. Conclusions: Because the smad7 expression pattern was similar to that of TGF-β, our study suggests that miR-21 can negatively regulate the frequency of circulating Treg cells through a TGF-β1/smad-independent signaling pathway in PBMCs.

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“…Emerging evidence suggests that miRs contribute to the pathogenesis of diabetes and diabetic complications (5,15,31,43). Since each miR has its potential targeting genes, information of miR involvement in diabetes is helpful for identification of the targeted molecules as well.…”

Section: Discussionmentioning

confidence: 99%

The SUR2B subunit of rat vascular K_ATP channel is targeted by miR-9a-3p induced by prolonged exposure to methylglyoxal

Jin

et al. 2015

American Journal of Physiology-Cell Physiology

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. The SUR2B subunit of rat vascular KATP channel is targeted by miR-9a-3p induced by prolonged exposure to methylglyoxal. Am J Physiol Cell Physiol 308: C139-C145, 2015. First published October 29, 2014; doi:10.1152/ajpcell.00311.2014.-ATP-sensitive K ϩ (KATP) channels regulate plasma membrane excitability. The Kir6.1/ SUR2B isoform of KATP channels is expressed in vascular smooth muscles and plays an important role in vascular tone regulation. This KATP channel is targeted by several reactive species. One of them is methylglyoxal (MGO), which is overly produced with persistent hyperglycemia and contributes to diabetic vascular complications. We have previously found that MGO causes posttranscriptional inhibition of the KATP channel, aggravating vascular tone regulation. Here we show evidence for the underlying molecular mechanisms. We screened microRNA databases and found several candidates. Of them, miR-9a-3p, increased its expression level by ϳ240% when the cultured smooth muscle cell line was exposed to micromolar concentrations of MGO. Treatments with exogenous miR-9a-3p downregulated the SUR2B but not Kir6.1 mRNA. Antisense nucleotides of miR9a-3p alleviated the effects of MGO. Quantitative PCR showed that the targeting sites of the miR-9a-3p were likely to be in the coding region of SUR2B. The effects of miR-9a-3p were mostly eliminated when the potential targeting site in SUR2B was site-specifically mutated. Our functional assays showed that KATP currents were impaired by miR-9a-3p induced with MGO treatment. These results suggest that MGO exposure raises the expression of miR-9a-3p, which subsequently downregulates the SUR2B mRNA, compromising KATP channel function in vascular smooth muscle.microRNA; ATP-sensitive potassium channel; diabetes DIABETES MELLITUS is a major challenge to biomedical sciences (12). Diabetes causes metabolic alterations leading to excessive production of various intermediary metabolites (4). One of them is methylglyoxal (MGO), a highly reactive carbonyl species (RCS) (2,16,39). MGO can react with proteins, nucleotides, and lipids, damaging these molecules and promoting inflammation and cell injuries (10,17,26). Normally, MGO is rapidly detoxified by metabolic and redox enzymes so that it is maintained at a rather low level (37). Under diabetic conditions, however, the increased production of precursor molecules and impaired carbonyl detoxification system result in overproduction and accumulation of this RCS (38). The imbalance in the production and clearance of RCS then leads to carbonyl stress, which is known to play an important role in the development of diabetic complications, especially in the vasculature (1, 7, 11).In the vasculature, an increase in MGO levels can impair structure and function of the vascular walls by acting on the vascular smooth muscle (VSM), endothelium, or both. This in turn disrupts the signaling network in these cells, triggers structural remodeling of the vascular wall, propagates vascular inflammation, and causes vascular dysfunction (40 -42). Ind...

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miR-21 overexpression enhances TGF-β1-induced epithelial-to-mesenchymal transition by target smad7 and aggravates renal damage in diabetic nephropathy

Cited by 138 publications

References 40 publications

TGF-β1 Induces Epithelial-Mesenchymal Transition of Chronic Sinusitis with Nasal Polyps through MicroRNA-21

TGF-β1 Induces Epithelial-Mesenchymal Transition of Chronic Sinusitis with Nasal Polyps through MicroRNA-21

MicroRNA-21 Negatively Regulates Treg Cells Through a TGF-β1/Smad-Independent Pathway in Patients with Coronary Heart Disease

The SUR2B subunit of rat vascular K_ATP channel is targeted by miR-9a-3p induced by prolonged exposure to methylglyoxal

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