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Dimethylaminomicheliolide ameliorates peritoneal fibrosis through the activation of autophagy

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Abstract

Peritoneal fibrosis (PF) is a major cause of ultrafiltration failure in patients receiving long-term peritoneal dialysis (PD), and effective prevention and treatment strategies are urgently needed. The dimethylamino Michael adduct of a natural product-derived micheliolide (MCL), dimethylaminomicheliolide (DMAMCL), is a new lead compound with the advantages of high stability, low toxicity, and sustainable release of MCL. This study aimed to investigate the protective effect of DMAMCL against PD-related PF and the mechanisms involved. In this study, we found that DMAMCL significantly decreased PD-induced extracellular matrix (ECM) deposition in a mouse model of PD, and that delayed DMAMCL administration halted the progression of PF in an established PD model. In addition, rapamycin administration induced autophagy and significantly ameliorated PF. The protective effect of DMAMCL against PF was weakened when co-administered with DMAMCL and 3-methyladenine. Inducing autophagy by rapamycin decreased transforming growth factor-β1–induced ECM accumulation in vitro. MCL promoted autophagy and inhibited ECM deposition. The anti-fibrotic effect of MCL was eliminated when knocking down ATG7 by siRNA. Taken together, DMAMCL might prevent against PF through activating autophagy. The anti-fibrotic effect of DMAMCL may be a new candidate for the treatment in patients with PD-related PF.

Key messages

  • Dimethylaminomicheliolide, the pro-drug of micheliolide, protects against peritoneal fibrosis in a mouse peritoneal dialysis model.

  • Micheliolide inhibits TGF-β1-induced extracellular matrix accumulation in vitro.

  • Autophagy plays a protective role against peritoneal fibrosis.

  • The antifibrogenic effect of dimethylaminomicheliolide may be due to the activation of autophagy.

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Acknowledgements

We thank Professor Xueqing Yu for providing the HMrSV5 cells and Accendatech Co., Ltd. (Tianjin, China) for providing DMAMCL and MCL.

Funding

This work was supported by the National Natural Science Foundation of China (NSFC) (no. 81673792, no. 81600624, no. 81704134, no.U1801288 and no. 81873346), the Natural Science Foundation of Guangdong Province, China (no. 2017A030313708 and no. 2014A030310065), Science and Technology Planning Project of Guangdong Province, China (no. 2014A020210011, no. 2015A020211012, and no. 2017A020215158), and Science and Technology Planning Project of Guangzhou, China (no. 201510010137 and no. 201707010286).

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  1. Shuting Li, Fenfen Peng and Wangqiu Gong contributed equally to this work.

Authors and Affiliations

  1. Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China

    Shuting Li, Fenfen Peng, Wangqiu Gong, Jiayu Wu, Wenting Liu, Hongyu Li, Bohui Yin, Congwei Luo, Peilin Li, Yihua Chen, Qianyin Huang, Weidong Zhou & Haibo Long

  2. Department of Gerontology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China

    Yuxian Wang

  3. Department of Emergency, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China

    Zhaozhong Xu

  4. Department of Nephrology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, China

    Ying Zhang

  5. Department of Nephrology, The First Hospital of Changsha, Changsha, 410000, China

    Sijia Chen

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  1. Shuting Li
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Correspondence to Weidong Zhou or Haibo Long.

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Li, S., Peng, F., Gong, W. et al. Dimethylaminomicheliolide ameliorates peritoneal fibrosis through the activation of autophagy. J Mol Med 97, 659–674 (2019). https://doi.org/10.1007/s00109-019-01757-1

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