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Dimethylaminomicheliolide ameliorates peritoneal fibrosis through the activation of autophagy

  • Shuting Li
  • Fenfen Peng
  • Wangqiu Gong
  • Jiayu Wu
  • Yuxian Wang
  • Zhaozhong Xu
  • Wenting Liu
  • Hongyu Li
  • Bohui Yin
  • Ying Zhang
  • Sijia Chen
  • Congwei Luo
  • Peilin Li
  • Yihua Chen
  • Qianyin Huang
  • Weidong ZhouEmail author
  • Haibo LongEmail author
Original Article
  • 61 Downloads

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.

Keywords

Peritoneal fibrosis Transforming growth factor-β1 Micheliolide Dimethylaminomicheliolide Autophagy 

Notes

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).

Compliance with ethical standards

Conflict of interest statement

The authors declare that they have no conflict of interest.

Supplementary material

109_2019_1757_MOESM1_ESM.docx (2.9 mb)
ESM 1 (DOCX 3011 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Shuting Li
    • 1
  • Fenfen Peng
    • 1
  • Wangqiu Gong
    • 1
  • Jiayu Wu
    • 1
  • Yuxian Wang
    • 2
  • Zhaozhong Xu
    • 3
  • Wenting Liu
    • 1
  • Hongyu Li
    • 1
  • Bohui Yin
    • 1
  • Ying Zhang
    • 4
  • Sijia Chen
    • 5
  • Congwei Luo
    • 1
  • Peilin Li
    • 1
  • Yihua Chen
    • 1
  • Qianyin Huang
    • 1
  • Weidong Zhou
    • 1
    Email author
  • Haibo Long
    • 1
    Email author
  1. 1.Department of Nephrology, Zhujiang HospitalSouthern Medical UniversityGuangzhouChina
  2. 2.Department of Gerontology, Zhujiang HospitalSouthern Medical UniversityGuangzhouChina
  3. 3.Department of Emergency, Zhujiang HospitalSouthern Medical UniversityGuangzhouChina
  4. 4.Department of Nephrology, The Second Affiliated HospitalGuangzhou Medical UniversityGuangzhouChina
  5. 5.Department of NephrologyThe First Hospital of ChangshaChangshaChina

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