SnoN as a novel negative regulator of TGF-β/Smad signaling: a target for tailoring organ fibrosis

Zeglinski, Matthew R.; Hnatowich, Mark; Jassal, Davinder S.; Dixon, Ian M.C.

doi:10.1152/ajpheart.00453.2014

Cited by 35 publications

(27 citation statements)

References 86 publications

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“…The previous reports demonstrated that SnoN interacts with Smad to block TGF-b1/Smad signaling, leading to suppressing the transcriptional activation of TGF-b1 target genes [31]. Therefore, SnoN negatively regulates the physiological effects of TGF-b1 [32][33][34].…”

Section: Discussionmentioning

confidence: 99%

Down-regulation of miR-23a inhibits high glucose-induced EMT and renal fibrogenesis by up-regulation of SnoN

Sun

et al. 2017

Human Cell

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It has been reported that transforming growth factor-β1 (TGF-β1) signaling plays an important role in the development of diabetic nephropathy (DN). The nuclear transcription co-repressor Ski-related novel protein N (SnoN) is a critical negative regulator of TGF-β1/Smad signal pathway, involving in tubule epithelial-mesenchymal transition (EMT), extracellular matrix (ECM) accumulation, and tubulointerstitial fibrosis. In this study, we focused on miR-23a as a regulator of SnoN. Our purpose is to study the effects of miR-23a on high glucose (HG)-induced EMT process and ECM deposition in HK2 cells. We found that miR-23a was up-regulated in renal tissues of diabetic patients and HG-induced HK2 cells. Besides, the high level of miR-23a was closely associated with decreased SnoN expression. Knockdown of miR-23a increased SnoN expression and in turn suppressed HG-induced EMT and renal fibrogenesis. Introduction of miR-23a decreased SnoN expression and enhanced the profibrogenic effects of HG on HK2 cells. Next, bioinformatics analysis predicted that the SnoN was a potential target gene of miR-23a. Luciferase reporter assay demonstrated that miR-23a could directly target SnoN. We demonstrated that overexpression of SnoN was sufficient to inhibit HG-induced EMT and renal fibrogenesis in HK2 cells. Furthermore, down-regulation of SnoN partially reversed the protective effect of miR-23a knockdown on HG-induced EMT and renal fibrogenesis in HK2 cells. Collectively, miR-23a and SnoN significantly impact on the progression of HG-induced EMT and renal fibrogenesis in vitro, and they may represent novel targets for the prevention strategies of renal fibrosis in the context of DN.

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Section: Discussionmentioning

confidence: 99%

Down-regulation of miR-23a inhibits high glucose-induced EMT and renal fibrogenesis by up-regulation of SnoN

Sun

et al. 2017

Human Cell

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“…Acutely following myocardial infarction (MI), the heart undergoes beneficial wound healing in which relatively inactive resident cardiac fibroblasts phenoconvert to hypersynthetic/secretory myofibroblasts that secrete comparatively more extracellular matrix (ECM or matrix) components including fibrillar collagen proteins (17,46). Increased matrix deposition at this time is required to provide additional structural and tensile strength to the myocardium to prevent cardiac rupture.…”

Section: -Mediated Induction Of Scleraxis Via Inhibition Of P42/ P44mentioning

confidence: 99%

TGFβ₁regulates Scleraxis expression in primary cardiac myofibroblasts by a Smad-independent mechanism

Zeglinski

Roché

Hnatowich

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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In cardiac wound healing following myocardial infarction (MI), relatively inactive resident cardiac fibroblasts phenoconvert to hypersynthetic/secretory myofibroblasts that produce large quantities of extracellular matrix (ECM) and fibrillar collagen proteins. Our laboratory and others have identified TGF␤ 1 as being a persistent stimulus in the chronic and inappropriate wound healing phase that is marked by hypertrophic scarring and eventual stiffening of the entire myocardium, ultimately leading to the pathogenesis of heart failure following MI. Ski is a potent negative regulator of TGF␤/Smad signaling with known antifibrotic effects. Conversely, Scleraxis is a potent profibrotic basic helix-loop-helix transcription factor that stimulates fibrillar collagen expression. We hypothesize that TGF␤ 1 induces Scleraxis expression by a novel Smad-independent pathway. Our data support the hypothesis that Scleraxis expression is induced by TGF␤ 1 through a Smad-independent pathway in the cardiac myofibroblast. Specifically, we demonstrate that TGF␤ 1 stimulates p42/44 (Erk1/2) kinases, which leads to increased Scleraxis expression. Inhibition of MEK1/2 using U0126 led to a sequential temporal reduction of phosphop42/44 and subsequent Scleraxis expression. We also found that adenoviral Ski expression in primary myofibroblasts caused a significant repression of endogenous Scleraxis expression at both the mRNA and protein levels. Thus we have identified a novel TGF␤ 1-driven, Smad-independent, signaling cascade that may play an important role in regulating the fibrotic response in activated cardiac myofibroblasts following cardiac injury.

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“…Cardiac interstitial fibrosis, the excessive deposition of extracellular matrix (ECM), is one of the major contributing factors in the pathogenesis of heart failure [2]. The excessive deposition of ECM proteins leads to poor cardiac performance due to disorganized electrical signaling and the inability to contract [3,4].…”

Section: Introductionmentioning

confidence: 99%

Cardiac Contractility Modulation Attenuate Myocardial Fibrosis by Inhibiting TGF-β1/Smad3 Signaling Pathway in a Rabbit Model of Chronic Heart Failure

Zhang

Dang

et al. 2016

Cell Physiol Biochem

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Backgroun/Aims: To explore the effect of cardiac contractility modulation (CCM) on myocardial fibrosis in heart failure and to investigate the underlying mechanism. Methods: Rabbits were randomly divided into sham group, HF group and CCM group. A rabbit model of chronic heart failure (CHF) was induced 12 weeks after aortic constriction by pressure unloading. Then cardiac contractility modulation was delivered to the myocardium lasting six hours per day for 4 weeks. Histology examination was carried out to evaluate the myocardial pathological changes. Protein levels of collagen I, collagen III, α-SMA, MMP2, MMP9, TIMP1, TGF-β1 and Smad3 were measured by western blot analysis. Results: Histology examination results showed that CCM therapy attenuated myocardial fibrosis and collagen deposition in rabbits with CHF. In addition, protein levels of collagen I, collagen III, α-SMA, MMP2, MMP9, TIMP1, TGF-β1 and Smad3 were down regulated. Conclusion: CCM therapy exerted protective effects against myocardial fibrosis potentially by inhibiting TGF-β1/Smad3 signaling pathway in CHF rabbits.

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SnoN as a novel negative regulator of TGF-β/Smad signaling: a target for tailoring organ fibrosis

Abstract: Zeglinski MR, Hnatowich M, Jassal DS, Dixon IM. SnoN as a novel negative regulator of TGF-␤/Smad signaling: a target for tailoring organ fibrosis.

Cited by 35 publications

References 86 publications

Down-regulation of miR-23a inhibits high glucose-induced EMT and renal fibrogenesis by up-regulation of SnoN

Down-regulation of miR-23a inhibits high glucose-induced EMT and renal fibrogenesis by up-regulation of SnoN

TGFβ₁regulates Scleraxis expression in primary cardiac myofibroblasts by a Smad-independent mechanism

Cardiac Contractility Modulation Attenuate Myocardial Fibrosis by Inhibiting TGF-β1/Smad3 Signaling Pathway in a Rabbit Model of Chronic Heart Failure

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SnoN as a novel negative regulator of TGF-β/Smad signaling: a target for tailoring organ fibrosis

Abstract: Zeglinski MR, Hnatowich M, Jassal DS, Dixon IM. SnoN as a novel negative regulator of TGF-␤/Smad signaling: a target for tailoring organ fibrosis.

Cited by 35 publications

References 86 publications

Down-regulation of miR-23a inhibits high glucose-induced EMT and renal fibrogenesis by up-regulation of SnoN

Down-regulation of miR-23a inhibits high glucose-induced EMT and renal fibrogenesis by up-regulation of SnoN

TGFβ1regulates Scleraxis expression in primary cardiac myofibroblasts by a Smad-independent mechanism

Cardiac Contractility Modulation Attenuate Myocardial Fibrosis by Inhibiting TGF-β1/Smad3 Signaling Pathway in a Rabbit Model of Chronic Heart Failure

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TGFβ₁regulates Scleraxis expression in primary cardiac myofibroblasts by a Smad-independent mechanism