The MicroRNA MiR-29c Alleviates Renal Fibrosis via TPM1-Mediated Suppression of the Wnt/β-Catenin Pathway

Huang, Huiya; Huang, Xiaozhong; Luo, Sai; Zhang, Huidi; Hu, Feifei; Chen, Ruyi; Huang, Chaoxing

doi:10.3389/fphys.2020.00331

Cited by 34 publications

(24 citation statements)

References 39 publications

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“…Accumulating evidence has demonstrated that inhibiting the Wnt signaling pathway could alleviate renal interstitial fibrosis by attenuating apoptosis and expression of fibrosis-associated markers in renal cells (Ren et al, 2019;Cai et al, 2020;Huang et al, 2020). Endogenous Wnt inhibitors can negatively regulate the Wnt signaling pathway by binding to Wnt ligands competitively with Wnt receptors or co-receptors, such as Dickkopf1 (DKK1), secreted frizzled protein 1 (Sfrp1), Wnt inhibitor 1 (Wif-1), Klotho (Kawazoe et al, 2021).…”

Section: Targeting Wnt/β-catenin Signaling As a Therapeutic Potential For Renal Fibrosismentioning

confidence: 99%

Targeting the Wnt/β-Catenin Signaling Pathway as a Potential Therapeutic Strategy in Renal Tubulointerstitial Fibrosis

Sun

Hua

et al. 2021

Front. Pharmacol.

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The Wnt/β-catenin signaling pathway plays important roles in embryonic development and tissue homeostasis. Wnt signaling is induced, and β-catenin is activated, associated with the development and progression of renal fibrosis. Wnt/β-catenin controls the expression of various downstream mediators such as snail1, twist, matrix metalloproteinase-7, plasminogen activator inhibitor-1, transient receptor potential canonical 6, and renin-angiotensin system components in epithelial cells, fibroblast, and macrophages. In addition, Wnt/β-catenin is usually intertwined with other signaling pathways to promote renal interstitial fibrosis. Actually, given the crucial of Wnt/β-catenin signaling in renal fibrogenesis, blocking this signaling may benefit renal interstitial fibrosis. There are several antagonists of Wnt signaling that negatively control Wnt activation, and these include soluble Fzd-related proteins, the family of Dickkopf 1 proteins, Klotho and Wnt inhibitory factor-1. Furthermore, numerous emerging small-molecule β-catenin inhibitors cannot be ignored to prevent and treat renal fibrosis. Moreover, we reviewed the knowledge focusing on anti-fibrotic effects of natural products commonly used in kidney disease by inhibiting the Wnt/β-catenin signaling pathway. Therefore, in this review, we summarize recent advances in the regulation, downstream targets, role, and mechanisms of Wnt/β-catenin signaling in renal fibrosis pathogenesis. We also discuss the therapeutic potential of targeting this pathway to treat renal fibrosis; this may shed new insights into effective treatment strategies to prevent and treat renal fibrosis.

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Section: Targeting Wnt/β-catenin Signaling As a Therapeutic Potential For Renal Fibrosismentioning

confidence: 99%

Targeting the Wnt/β-Catenin Signaling Pathway as a Potential Therapeutic Strategy in Renal Tubulointerstitial Fibrosis

Sun

Hua

et al. 2021

Front. Pharmacol.

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“…Many studies have identified fibrosis-related targets of miR-29 under hyperglycemic conditions, demonstrating the anti-fibrotic role of miR-29 in DKD. Insterestingly, studies also revealed that miR-29c, serves as a signature miRNA that promotes the progression of DN and fibrosis ( Long et al, 2011 ; Shao et al, 2019 ; Huang et al, 2020 ). More and more studies are revealing the functions and mechanisms of miRNAs in fibrosis and inflammation during diabetic conditions, these miRNAs may play as potential therapeutic targets to combat DKD.…”

Section: Tgf-β/smad-dependent Non-coding Rnas In Dkdmentioning

confidence: 99%

Non-Coding RNAs as Biomarkers and Therapeutic Targets for Diabetic Kidney Disease

Huang

et al. 2021

Front. Pharmacol.

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Diabetic kidney disease (DKD) is the most common diabetic complication and is a leading cause of end-stage kidney disease. Increasing evidence shows that DKD is regulated not only by many classical signaling pathways but also by epigenetic mechanisms involving chromatin histone modifications, DNA methylation, and non-coding RNA (ncRNAs). In this review, we focus on our current understanding of the role and mechanisms of ncRNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) in the pathogenesis of DKD. Of them, the regulatory role of TGF-β/Smad3-dependent miRNAs and lncRNAs in DKD is highlighted. Importantly, miRNAs and lncRNAs as biomarkers and therapeutic targets for DKD are also described, and the perspective of ncRNAs as a novel therapeutic approach for combating diabetic nephropathy is also discussed.

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“…It has been confirmed that TGF-β1 induces the epithelial-mesenchymal transition (EMT) and causes ECM to be excessively deposited as collagen [ 15 – 17 ]. According to recent studies, Wnt/β-catenin signalling and TGF-β1 are the most powerful mediators that promote EMT; both increase the secretion of collagen and other ECM proteins by mesenchymal cells, inhibit ECM degradation and ultimately result in ECM deposition in damaged tissues and organs [ 11 , 18 , 19 ]. High expression of TGF-β1 has been demonstrated both in clinical samples from humans with IUAs and in animal IUA models [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

si-SNHG5-FOXF2 inhibits TGF-β1-induced fibrosis in human primary endometrial stromal cells by the Wnt/β-catenin signalling pathway

Liu

Chen

et al. 2020

Stem Cell Res Ther

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Background Intrauterine adhesions (IUAs) are manifestations of endometrial fibrosis characterized by inflammation and fibrinogen aggregation in the extracellular matrix (ECM). The available therapeutic interventions for IUA are insufficiently effective in the clinical setting for postoperative adhesion recurrence and infertility problems. In this study, we investigated whether si-SNHG5-FOXF2 can serve as a molecular mechanism for the inhibition of IUA fibrosis ex vivo. Methods FOXF2, TGF-β1 and collagen expression levels were measured by microarray sequencing analysis in three normal endometrium groups and six IUA patients. We induced primary human endometrial stromal cells (HESCs) into myofibroblasts (MFs) to develop an IUA cell model with various concentrations of TGF-β1 at various times. Downstream target genes of FOXF2 were screened by chromatin immunoprecipitation combined with whole-genome high-throughput sequencing (ChIP-seq). We investigated ECM formation, cell proliferation and Wnt/β-catenin signalling pathway-related proteins in primary HESCs with FOXF2 downregulation by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), western blotting (WB), immunohistochemistry (IHC), flow cytometry, ethylenediurea (EdU) and CCK8 assays. We identified long noncoding RNAs (lncRNA) SNHG5 as the upstream regulatory gene of FOXF2 through RNA immunoprecipitation (RIP), RNA pulldown and fluorescence in situ hybridization (FISH). Finally, we examined FOXF2 expression, ECM formation, cell proliferation and Wnt/β-catenin signalling pathway-related proteins in primary HESCs upon FOXF2 downregulation. Results FOXF2 was highly expressed in the endometrium of patients with IUA. Treatment of primary HESCs with 10 ng/ml TGF-β1 for 72 h was found to be most effective for developing an IUA cell model. FOXF2 regulated multiple downstream target genes, including collagen, vimentin (VIM) and cyclin D2/DK4, by ChIP-seq and ChIP-PCR. FOXF2 downregulation inhibited TGF-β1-mediated primary HESC fibrosis, including ECM formation, cell proliferation and Wnt/β-catenin signalling pathway-related protein expression. We identified lncRNA SNHG5 as an upstream gene that directly regulates FOXF2 by RIP-seq, qRT-PCR, WB and FISH. SNHG5 downregulation suppressed FOXF2 expression in the IUA cell model, resulting in synergistic repression of the Wnt/β-catenin pathway, thereby altering TGF-β1-mediated ECM aggregation in endometrial stromal cells ex vivo. Conclusions Regulation of the Wnt/β-catenin signalling pathway and ECM formation by si-SNHG5-FOXF2 effectively inhibited the profibrotic effect of TGF-β1 on primary HESCs. This finding can provide a molecular basis for antagonizing TGF-β1-mediated fibrosis in primary HESCs.

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The MicroRNA MiR-29c Alleviates Renal Fibrosis via TPM1-Mediated Suppression of the Wnt/β-Catenin Pathway

Cited by 34 publications

References 39 publications

Targeting the Wnt/β-Catenin Signaling Pathway as a Potential Therapeutic Strategy in Renal Tubulointerstitial Fibrosis

Targeting the Wnt/β-Catenin Signaling Pathway as a Potential Therapeutic Strategy in Renal Tubulointerstitial Fibrosis

Non-Coding RNAs as Biomarkers and Therapeutic Targets for Diabetic Kidney Disease

si-SNHG5-FOXF2 inhibits TGF-β1-induced fibrosis in human primary endometrial stromal cells by the Wnt/β-catenin signalling pathway

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