MicroRNA-27a targets Sfrp1 to induce renal fibrosis in diabetic nephropathy by activating Wnt/β-Catenin signalling

Shi, Mingjun; Tian, PingPing; Liu, Zhongqiang; Zhang, Fan; Zhang, Yingying; Qu, Lingling; Liu, Xingmei; Wang, Yuanyuan; Zhou, Xingcheng; Xiao, Ying; Guo, Bing

doi:10.1042/bsr20192794

Cited by 22 publications

(12 citation statements)

References 41 publications

(53 reference statements)

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“…We also observed that the WNT/β-catenin pathway was activated: the total protein and nucleoprotein expressions of β-catenin in the HG condition were both higher than those in the NG condition. The same phenomenon was observed in rat kidney cells cultured with high glucose ( 25 ). After the WNT pathway is activated, β-catenin enters the cell nucleus and combines with the transcription factor TCF/LEFs to initiate the transcriptional regulation of multiple target genes, including c-Myc ( 26 ).…”

Section: Discussionsupporting

confidence: 74%

c-Myc Upregulated by High Glucose Inhibits HaCaT Differentiation by S100A6 Transcriptional Activation

et al. 2021

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Keratinocyte differentiation dysfunction in diabetic skin is closely related to impaired skin barrier functions. We investigated the effects of c-Myc and S100A6 on Human immortal keratinocyte line (HaCaT) or keratinocyte differentiation and potential mechanisms. The expression levels of differentiation makers such as transglutaminase 1 (TGM1), loricrin (LOR), and keratin 1 (K1) were significantly reduced, while the expression of c-Myc was significantly increased in HaCaT cells cultured in high glucose and wound margin keratinocytes from diabetic rats and human patients. Overexpression of c-Myc caused differentiation dysfunction of HaCaT, while knocking down c-Myc promoted differentiation. High glucose increased the expression of c-Myc and inhibited differentiation in HaCaT cells by activating the WNT/β-catenin pathway. Moreover, inhibition of c-Myc transcriptional activity alleviated the differentiation dysfunction caused by high glucose or overexpression of c-Myc. c-Myc binds to the S100A6 promoter to directly regulate S100A6 expression and high glucose promoted S100A6 transcription. The expression of S100A6 was increased in HaCaT cultured with high glucose and wound margin keratinocytes from diabetic rats and human patients. However, the expression of S100A6 was decreased during normal HaCaT differentiation. HaCaT cells treated with S100A6 recombinant protein showed differentiation dysfunction. The expressions of TGM1, LOR and K1 in knockdown S100A6 HaCaT cells were higher than those in the control group. Overexpression of c-Myc or high glucose caused differentiation dysfunction of HaCaT cells, and was rescued by knocking down S100A6. These findings illustrate a new mechanism by which c-Myc upregulated by high glucose inhibits HaCaT differentiation by directly activating S100A6 transcription. Thus, c-Myc and S100A6 may be potential targets for the treatment of chronic diabetic wounds.

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Section: Discussionsupporting

confidence: 74%

c-Myc Upregulated by High Glucose Inhibits HaCaT Differentiation by S100A6 Transcriptional Activation

et al. 2021

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“…22 Several miRs have been reported as fibrosis promoters and underlying prognostic markers in diabetes or diabetes-related complications, such as miR-27a and miR-135a. 23,24 Li et al found that the pathological silencing of miR-32 could improve hepatic fibrosis. 25 However, there was no direct evidence to support the role of miR-32 in DN fibrosis.…”

Section: Discussionmentioning

confidence: 99%

MiR-32-5p knockdown inhibits epithelial to mesenchymal transition and renal fibrosis by targeting SMAD7 in diabetic nephropathy

et al. 2020

Hum Exp Toxicol

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Diabetic nephropathy (DN) is primary cause of end-stage renal disease. A previous study has shown that miR-32-5p (miR-32) is highly expressed in kidney tissue during chronic allograft dysfunction with interstitial fibrosis and tubular atrophy. However, the role of miR-32-5p (miR-32) in DN is still unclear. In this study, streptozotocin-induced DN rat models and high glucose (HG)-incubated human kidney proximal tubular epithelial (HK-2) cells were established to investigate the role and underlying mechanisms of miR-32 in DN. Results of real-time PCR revealed that miR-32 levels were greatly increased in DN rats and HG-incubated HK-2 cells. Downregulation of miR-32 effectively relieved HG-induced autophagy suppression, fibrosis, epithelial-mesenchymal transition (EMT) and inflammation in HK-2 cells. Besides, miR-32 overexpression significantly down-regulated the expression of mothers against decapentaplegic homolog 7 (SMAD7), whereas knockdown of miR-32 markedly up-regulated the level of SMAD7. Dual-luciferase reporter gene assay confirmed that SMAD7 was a target of miR-32. Reintroduction of SMAD7 expression rescued miR-32-induced HK-2 cells autophagy suppression, EMT and renal fibrosis. Our findings indicate that miR-32 may play roles in the progression of EMT and fibrosis in DN.

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“…miR-21 not only suppresses the inhibitory Smad7 of TGF-β signaling to promote fibrosis (Zhong et al, 2013;Wang et al, 2014) but also targeting the Sprouty (SPRY) to activate the Ras/MEK/ERK signaling to activate fibrogenesis of TGF-β signaling (Xu et al, 2014). In addition, miR-21 also exerts profibrotic and pro-inflammatory Anti/pro-fibrosis (Kato et al, 2007;Chung et al, 2010;Krupa et al, 2010;Kato et al, 2011b;Putta et al, 2012;Deshpande et al, 2013;Ma et al, 2016;Liu et al, 2018) (Zhong et al, 2011;Wang et al, 2013;Zhong et al, 2013;Wang et al, 2014;Lai et al, 2015;Mcclelland et al, 2015;Kölling et al, 2017;Chen et al, 2018) Pro-inflammation miR-27a SFRP1; PRKAA2; PPARγ Pro-fibrosis (Hou et al, 2016;Wu et al, 2018b;Shi et al, 2020) miR-130b TGF-β1; Smad2/3; Smad4 (Castro et al, 2014;Lv et al, 2015;Liu et al, 2019b;Ma et al, 2019b) effects by targeting PTEN, tissue inhibitor of matrix metalloproteinases (TIMPs), and other molecules, as shown in Table 3.…”

Section: Tgf-β/smad-dependent Mirnas In Renal Fibrosis and Inflammation 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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MicroRNA-27a targets Sfrp1 to induce renal fibrosis in diabetic nephropathy by activating Wnt/β-Catenin signalling

Cited by 22 publications

References 41 publications

c-Myc Upregulated by High Glucose Inhibits HaCaT Differentiation by S100A6 Transcriptional Activation

c-Myc Upregulated by High Glucose Inhibits HaCaT Differentiation by S100A6 Transcriptional Activation

MiR-32-5p knockdown inhibits epithelial to mesenchymal transition and renal fibrosis by targeting SMAD7 in diabetic nephropathy

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

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