HDAC5-mediated Smad7 silencing through MEF2A is critical for fibroblast activation and hypertrophic scar formation

Gao, Ya; Liu, Yangdan; Zheng, Duo; Ho, Chia-Kang; Wen, Dongsheng; Sun, Jiaming; Huang, Lujun; Liu, Yuxin; Li, Qingfeng; Zhang, Yifan

doi:10.7150/ijbs.76140

Cited by 28 publications

(18 citation statements)

References 51 publications

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“…21,30 MEF2A is critical for the transcription regulation of Smad7 expression. 20 MEF2A is a transcription factor that plays an important role in the regulation of muscle development and function. 31,32 However, its role in renal fibrosis has not been fully studied.…”

Section: Discussionmentioning

confidence: 99%

“…Studies have shown that HDAC5 can repress the transcription of Smad7 by repressing the transcriptional activity of MEF2A. 20,21 To verify this, we first examined the impact of HDAC5 knockdown under TGF-β stimulation and found that MEF2A expression also decreased, while Smad7 expression was recovered. These results demonstrate that HDAC5 regulated both MEF2A and Smad7 (Figure 6A-C).…”

Section: Hdac5 Interacted With Mef2a To Repress Smad7 Transcriptional...mentioning

confidence: 92%

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GRK5 promoted renal fibrosis via HDAC5/Smad3 signaling pathway

Xiang,

Huang,

Song

et al. 2024

The FASEB Journal

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Renal fibrosis is a common pathological feature of chronic kidney diseases (CKD), poses a significant burden in the aging population, and is a major cause of end‐stage renal disease (ESRD). In this study, we investigated the role of G protein‐coupled receptor kinases (GRKs) 5 in the pathogenesis of renal fibrosis. GRK5 is a serine/threonine kinase that regulates G protein‐coupled receptor (GPCR) signaling. GRK5 has been shown to play a role in various diseases including cardiac disorders and cancer. However, the role of GRK5 in renal fibrosis remains largely unknown. Our finding revealed that GRK5 was significantly overexpressed in renal fibrosis. Specifically, GRK5 was transferred into the nucleus via its nuclear localization sequence to regulate histone deacetylases (HDAC) 5 expression under renal fibrosis. GRK5 acted as an upstream regulator of HDAC5/Smad3 signaling pathway. HDAC5 regulated and prevented the transcriptional activity of myocyte enhancer factor 2A (MEF2A) to repress the transcription of Smad7 which leading to the activation of Smad3. These findings first revealed that GRK5 may be a potential therapeutic target for the treatment of renal fibrosis. Inhibition of GRK5 activity may be a promising strategy to attenuate the progression of renal fibrosis.

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Section: Discussionmentioning

confidence: 99%

Section: Hdac5 Interacted With Mef2a To Repress Smad7 Transcriptional...mentioning

confidence: 92%

GRK5 promoted renal fibrosis via HDAC5/Smad3 signaling pathway

Xiang,

Huang,

Song

et al. 2024

The FASEB Journal

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“…[39] Recently, Ya Gao et al reported that LMK235 signi cantly alleviated hypertrophic scar formation in vivo, and HDAC5 knockdown inhibited TGF-β1-induced Smad2/3 phosphorylation and broblast activation in vitro. [40] Therefore, we hypothesized that LMK235 could suppress TGF-β1-induced broblast-myo broblast transformation by inhibiting Smad2/3 pathway activation in cardiac broblasts. In our study, we con rmed that LMK235 attenuated TGF-β1-induced broblast-myo broblast transformation by inhibiting Smad2/3 pathway activation.…”

Section: Discussionmentioning

confidence: 99%

LMK235 ameliorates ventricular remodelling after myocardial infarction by targeting cardiac fibroblasts and macrophages

2023

Preprint

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Objectives Histone deacetylase 4 (HDAC4)and histone deacetylase 5 (HDAC5) are two isoforms of class IIa HDACs, LMK235 is an HDAC inhibitor with higher selectivity forHDAC4/5. Here, we aimed to explorethe effects of LMK235 on ventricular remodelling after myocardial infarction (MI). Methods The MI model was established by left anterior descending branch ligation. The effects of LMK235 on cardiac dysfunction was determined by echocardiography and left ventricular pressure measurement. Fibrosis was evaluated by Masson staining and fibrotic biomarker expression, inflammation was evaluated by HE staining and inflammatory cytokine expression. In vitro, myofibroblast transformation was induced by transforming growth factor-β1 (TGF-β1) stimulation in primary mouse cardiac fibroblasts (MCFs), and macrophage polarization was induced by lipopolysaccharide (LPS) stimulation in RAW264.7 cells. Western blotting, immunofluorescence, flow cytometry were performed to examine the effects of LMK235. Key findings LMK235 ameliorated cardiac dysfunction post-MI by suppressing fibrosisand inflammation. In MCFs, LMK235 attenuated TGF-β1-induced fibrotic biomarker expression by inhibiting Smad2/3 pathway. In RAW264.7 cells, LMK235 attenuated LPS-induced inflammatory cytokine expression by inhibiting NF-κB pathway. Conclusions LMK235 can attenuate fibrosis post-MI by inhibiting Smad2/3 pathway in cardiac fibroblasts, and attenuate inflammation post-MI by inhibiting NF-κB pathway in macrophages, leading to improved cardiac function.

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“…HDAC5 is a member of the class IIa family histone deacetylase family, and it has been discovered to be closely related to the fibrosis; it can activate fibroblasts and facilitated the formation of hypertrophic scar. [ 30 ] In lung fibrosis tissues of mouse, the significantly upregulated HDAC5 has been researched. [ 31 ] Thus, HDAC5 is identified to be key gene involved in regulating fibrosis.…”

Section: Discussionmentioning

confidence: 99%

SNHG16/miR‐205/HDAC5 is involved in the progression of renal fibrosis

Zhao,

Wang,

Tang

et al. 2023

J Biochem & Molecular Tox

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Renal interstitial fibrosis (RIF) represents an irreversible and progressive pathological manifestation of chronic renal disease, which ultimately leads to end‐stage renal disease. Long noncoding RNAs (lncRNAs) have been suggested to be involved in the progression of RIF. Small nucleolar RNA host gene 16 (SNHG16), a member of lncRNAs, has been found to be involved in the progression of pulmonary fibrosis. This paper first researched the effect of SNHG16 on renal fibrosis. We established a unilateral ureteral obstruction (UUO)‐induced mouse RIF model by ligation of the left ureter to evaluate the biological function of SNHG16 in RIF. As a result, SNHG16 was upregulated in UUO‐induced renal fibrotic tissues. Knockdown of SNHG16 inhibited RIF and reduced alpha‐smooth muscle actin (α‐SMA), fibronectin, and college IV expression. miR‐205 was a target of SNHG16, and downregulated in UUO‐induced renal fibrotic tissues. Inhibition of miR‐205 promoted RIF and increased the expression of α‐SMA, college IV, and fibronectin. Overexpression of SNHG16 promoted the UUO‐induced RIF, but miR‐205 abrogated this effect of SNHG16. Histone deacetylase 5 (HDAC5) showed high expression in UUO‐induced renal fibrotic tissues. Knockdown of HDAC5 significantly reduced α‐SMA, fibronectin, and college IV expression in renal tissues of UUO‐induced mice. Inhibition of miR‐205 promoted HDAC5 expression, but knockdown of SNHG16 inhibited HDAC5 expression in renal tissues of UUO‐induced mice. In conclusion, SHNG16 is highly expressed in renal fibrotic tissues of UUO‐induced mice. Knockdown of SHNG16 may prevent UUO‐induced RIF by indirectly upregulating HDAC5 via targeting miR‐205. SHNG16 may be novel target for treating renal fibrosis.

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HDAC5-mediated Smad7 silencing through MEF2A is critical for fibroblast activation and hypertrophic scar formation

Cited by 28 publications

References 51 publications

GRK5 promoted renal fibrosis via HDAC5/Smad3 signaling pathway

GRK5 promoted renal fibrosis via HDAC5/Smad3 signaling pathway

LMK235 ameliorates ventricular remodelling after myocardial infarction by targeting cardiac fibroblasts and macrophages

SNHG16/miR‐205/HDAC5 is involved in the progression of renal fibrosis

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