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Smad2 protects against TGF-β1/Smad3-mediated collagen synthesis in human hepatic stellate cells during hepatic fibrosis

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Abstract

With structural similarity but functional diversity, Smad2 and Smad3 interact with each other to mediate transforming growth factor-β (TGF-β)-triggered signaling transduction. However, in the hepatic fibrosis, the detailed roles of R-Smads, and interaction between Smad2 and Smad3 are still undefined. In this setting, we established a rat model of CCl4-induced hepatic fibrosis in vivo and TGF-β1-treated hepatic stellate cell model in vitro to detect whether Smad2 and Smad3 play distinct roles in mediating liver fibrogenesis. Results indicated that both phosphorylation of Smad2 and Smad3 were detected in the hepatic stellate cells of liver fibrotic tissues and cells. Furthermore, In vitro data demonstrated that knockdown of Smad2 in human hepatic stellate cells increased expression of collagen I (Col.I), tissue inhibitor of metalloproteinase-1 (TIMP-1) whereas decreasing expression of the matrix metalloproteinases-2(MMP-2) in presence of TGF-β1 compared with control group. In contrast, knockdown of Smad3 significantly reduced TGF-β1-induced Col.I production. These findings were further evident by the results that overexpression of Smad2 attenuated the expression of Col.I and TIMP-1, but enhanced MMP-2 whereas overexpression of Smad3 showed the opposite effect. Furthermore, Smad2 suppressed the phosphorylation and nuclear translocation of Smad3, which may protect against Smad3-mediated fibrotic response. Collectively, Smad2 may be a potential therapeutic target for the treatment of hepatic fibrosis.

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Abbreviations

TGF-β1:

Transforming growth factor-β1

TIMP-1:

Issue inhibitor of metalloproteinase 1

MMP-2:

Matrix-degrading enzyme 2

EMT:

Epithelial-to-mesenchymal transition

ECM:

Extracellular matrix

KO:

Knockout

SMAD2:

Mothers against decapentaplegic homolog 2

SMAD3:

Mothers against decapentaplegic homolog 3

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Acknowledgments

This work was supported by the Chinese National Natural Science Foundation Project (81100302) and Intercollegiate Key Projects of Nature Science of Anhui Province (KJ2011A174).

Conflict of interest

The authors declare that there are no conflicts of interest.

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Authors and Affiliations

  1. School of Pharmacy, Anhui Medical University, Hefei, 230032, China

    Lei Zhang, Changwei Liu, Xiao-ming Meng, Cheng Huang, Fengyun Xu & Jun Li

  2. Institute for Liver Diseases of Anhui Medical University (AMU), Hefei, China

    Lei Zhang, Changwei Liu, Xiao-ming Meng, Cheng Huang, Fengyun Xu & Jun Li

Authors
  1. Lei Zhang
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  2. Changwei Liu
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  3. Xiao-ming Meng
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  4. Cheng Huang
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  5. Fengyun Xu
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  6. Jun Li
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Corresponding author

Correspondence to Jun Li.

Additional information

Lei Zhang and Changwei Liu have contributed equally to the manuscript.

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Zhang, L., Liu, C., Meng, Xm. et al. Smad2 protects against TGF-β1/Smad3-mediated collagen synthesis in human hepatic stellate cells during hepatic fibrosis. Mol Cell Biochem 400, 17–28 (2015). https://doi.org/10.1007/s11010-014-2258-1

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  • DOI: https://doi.org/10.1007/s11010-014-2258-1

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