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Ascochlorin suppresses TGF-β1-induced PAI-1 expression through the inhibition of phospho-EGFR in rat kidney fibroblast cells

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Abstract

Fibrosis is induced by the excessive and abnormal deposition of extracellular matrix (ECM) with various growth factors in tissues. Transforming growth factor-β1 (TGF-β1), the growth factor involved in fibrosis, modulates ECM synthesis and accumulation. TGF-β1 enhances the production of stimulators of ECM synthesis such as plasminogen activator inhibitor type 1 (PAI-1). As such, PAI-1 expression directly influences the proteolysis, invasion, and accumulation of ECM. It was shown in this study that ascochlorin, a prenylpenl antiobiotic, prevents the expression of profibrotic factors, such as PAI-1 and collagen type I, and that the TGF-β1-induced PAI-1 promoter activity is inhibited by ascochlorin. Ascochlorin abolishes the phosphorylation of the EGFR-MEK-ERK signaling pathway to regulate the TGF-β1-induced expression of PAI-1 without the inhibition of TβRII phosphorylation. Furthermore, the MEK inhibitor and EGFR siRNA block PAI-1 expression, and the Raf-1, MEK, and ERK signaling pathways for the regulation of PAI-1 expression. Ascochlorin suppresses the matrix metalloproteinases (MMPs) activity to activate the heparin-binding EGF-like growth factor (HB-EGF), to induce the phosphorylation of EGFR, and the MMPs inhibitor suppresses EGFR phosphorylation and the PAI-1 mRNA levels. These results suggest that ascochlorin prevents the expression of PAI-1 via the inhibition of an EGFR-dependent signal transduction pathway activated by MMPs.

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Abbreviations

PAI-1:

Plasminogen activator inhibitor-1

EGFR:

Epidermal growth factor receptor

MMP:

Matrix metalloproteinase

TGF-β:

Transforming growth factor-β

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Acknowledgments

This stuay was supported by the Grant of the Korean Ministry of Education, Science and Technology (The Regional Core Research Program/Anti-aging and Well-being Research Center).

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Authors and Affiliations

  1. Research Institute of Biomedical Engineering and Department of Medicine, Catholic University of Daegu School of Medicine, 3056-6, Daemyung-4-Dong, Nam-gu, Daegu, 705-718, Republic of Korea

    Hyun-Ji Cho, Jeong-Han Kang, Ji-Hak Jeong, Yun-Jeong Jeong, Kwan-Kyu Park, Yoon-Yub Park, Yong-Suk Moon, Hong-Tae Kim & Young-Chae Chang

  2. Department of Biotechnology, Catholic University of Daegu, Gyeongsan, 712-702, Republic of Korea

    Il-Kyung Chung

  3. Department of Biological Science, Sungkyunkwan University, Suwon, Kyunggi-Do, 440-746, Republic of Korea

    Cheorl-Ho Kim

  4. College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea

    Hyeun-Wook Chang

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  1. Hyun-Ji Cho
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Correspondence to Young-Chae Chang.

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Cho, HJ., Kang, JH., Jeong, JH. et al. Ascochlorin suppresses TGF-β1-induced PAI-1 expression through the inhibition of phospho-EGFR in rat kidney fibroblast cells. Mol Biol Rep 39, 4597–4603 (2012). https://doi.org/10.1007/s11033-011-1251-y

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