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Ochratoxin A induces epithelial-to-mesenchymal transition and renal fibrosis through TGF-β/Smad2/3 and Wnt1/β-catenin signaling pathways in vitro and in vivo

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Abstract

Ochratoxin A (OTA) is a toxin produced by fungi such as Aspergillus spp. and Penicillium spp. The key target organ of OTA toxicity is the kidney, and it is known that epithelial-to-mesenchymal transition (EMT) leading to fibrosis is enhanced after long-term exposure of the kidney to OTA. However, the mechanisms responsible for this onset are not precisely known. Therefore, the purpose of this study was to investigate the mechanism of OTA-induced EMT and fibrosis in human proximal tubule HK-2 cells and mouse kidneys. Cells were treated for 48 h with various concentrations of OTA (50, 100, and 200 nM) and mice underwent oral administration of various doses of OTA (200 and 1000 μg/kg body weight) for 12 weeks. Blood urea nitrogen and creatinine levels were increased in the serum of OTA-treated mice, and fibrosis was observed in kidney tissues. Furthermore, alpha-smooth muscle actin (α-SMA) and fibronectin levels were increased, and E-cadherin level was decreased by OTA in both HK-2 cells and kidney tissues. In addition, the expression levels of TGF-β, smad2/3, and β-catenin were increased after OTA treatment. α-SMA, E-cadherin, and fibronectin were shown to be regulated by the activation of transcription factors, smad2/3 and β-catenin. These results demonstrated that OTA induces EMT and renal fibrosis through Smad2/3 and β-catenin signaling pathways in vitro and in vivo.

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Acknowledgements

This research was supported by the International Joint R&D Program (Q1624243) of the Agency for Korean National Food Cluster, Republic of Korea; a Korea University Grant (K2009551) from the School of Life Sciences, Republic of Korea; and the Biotechnology of Korea University for BK21PLUS, Republic of Korea. The authors would like to thank the Institute of Biomedical Science & Food Safety, CJ-Korea University Food Safety Hall (Seoul, Republic of Korea) for providing the equipment and facilities.

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  1. Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Anam-dong, Seongbuk-gu, Seoul, 02841, Republic of Korea

    Min Cheol Pyo, Seung A. Chae, Hee Joon Yoo & Kwang-Won Lee

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Study concept and design: MCP and K-WL. Analysis and interpretation of data: MCP and K-WL. Drafting of the manuscript: MCP, K-WL, SAC, and HJY. Final approval of the manuscript: K-WL. All authors read and approved the final manuscript.

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Correspondence to Kwang-Won Lee.

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Pyo, M.C., Chae, S.A., Yoo, H.J. et al. Ochratoxin A induces epithelial-to-mesenchymal transition and renal fibrosis through TGF-β/Smad2/3 and Wnt1/β-catenin signaling pathways in vitro and in vivo. Arch Toxicol 94, 3329–3342 (2020). https://doi.org/10.1007/s00204-020-02829-9

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