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TRIM46 upregulates Wnt/β-catenin signaling by inhibiting Axin1 to mediate hypoxia-induced epithelial–mesenchymal transition in HK2 cells

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Abstract

Hypoxia can cause Epithelial–mesenchymal transition (EMT) in renal tubular cells, and in turn, renal fibrosis. We tested the expression of TRIM46, a member of tripartite motif-containing (TRIM) family proteins, and mesenchymal markers under hypoxia. Our results showed that hypoxia significantly enhanced expression of TRIM46 in HK2 human renal proximal tubular epithelial cells. Our data further showed that hypoxia led to upregulated expression of mesenchymal markers including α-smooth muscle actin, vimentin, and Snail, and downregulated expression of epithelial marker E-cadherin, coupled with an increased abundance of nuclear β-catenin. However, such effects were reversed when TRIM46 expression was knocked down. TRIM46 overexpression had similar effects as hypoxia exposure, and such effects were reversed when cells were treated with XAV-939, a selective inhibitor for β-catenin. Furthermore, we found that TRIM46 promoted ubiquitination and proteasomal degradation of Axin1 protein, a robust negative regulator of Wnt/β-catenin signaling activity. Finally, increased TRIM46 coupled with decreased Axin1 was observed in a rat renal fibrosis model. These data suggest a novel mechanism contributing to EMT that mediates hypoxia-induced renal fibrosis. Our results suggest that selectively inhibiting this pathway that activates fibrosis in human kidney may lead to development of a novel therapeutic approach for managing this disease.

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Data availability

The datasets generated during the current study are available from the corresponding author on reasonable request.

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Funding

This study was supported by Summit Discipline of Clinical Traditional Chinese Medicine in Pudong New Area of Shanghai (PDZY-2018-0601) and National Natural Science Foundation of China (82074261).

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Author notes

  1. Lin Liao and Baojuan Zhou have contributed equally to this work.

Authors and Affiliations

  1. Department of Nephrology, Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, No.358 Datong Road in Pudong New District, Shanghai, 200137, China

    Lin Liao, Lianxiang Duan, Yue Guo, Baojuan Zhou, Qiming Xu, Chuanfu Zhang, Weiwei Liu, Wenrui Liu, Ziyang Liu, Jing Hu, Jie Chen & Jianrao Lu

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  1. Lin Liao
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Contributions

JC and JL contributed to the study conception and design. Material preparation, data collection, and analysis were performed by LL, L D, YG, BZ, QX, CZ, WL, WL, ZL, and JH. The first draft of the manuscript was written by LL and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Jie Chen or Jianrao Lu.

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The authors have no relevant financial or non-financial interests to disclose.

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This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Animal Care Committee of Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine.

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Liao, L., Duan, L., Guo, Y. et al. TRIM46 upregulates Wnt/β-catenin signaling by inhibiting Axin1 to mediate hypoxia-induced epithelial–mesenchymal transition in HK2 cells. Mol Cell Biochem 477, 2829–2839 (2022). https://doi.org/10.1007/s11010-022-04467-4

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