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Parthenolide alleviates peritoneal fibrosis by inhibiting inflammation via the NF-κB/ TGF-β/Smad signaling axis

Abstract

Peritoneal fibrosis is a common complication of peritoneal dialysis (PD) with a complicated pathogenesis and limited treatments. Parthenolide (PTL), a recognized nuclear factor-κB (NF-κB) inhibitor extracted from Tanacetum balsamita, has been widely used to treat various inflammatory diseases and has been proven to improve peritoneal fibrosis in PD mice by selectively inhibiting the phosphorylation of Smad2/3. Transforming growth factor-β1 (TGF-β1), via Smad-dependent signaling, has a pivotal role in promoting pathogenic of fibrosis. To investigate whether PTL can inhibit peritoneal fibrosis, we affected the interaction between NF-κB and the TGF-β/Smad2/3 pathway. Long dwell peritoneal dialysis fluid (PDF) and peritoneum tissues were collected from continuous ambulatory peritoneal dialysis (CAPD) patients. PTL was administered intragastrically into a PD mouse model by daily infusion of 4.25% dextrose-containing PDF. Treated HMrSV5 cells or rat peritoneal mesothelial cells (RPMCs) were treated with high glucose(138 mM) at the same concentration as 2.5% dextrose-containing PDF and PTL. PD-related peritoneal fibrosis samples indicated an increase in inflammation, and PTL decreased the levels of inflammatory cytokines (L-6, TNF-α, and MCP-1). PTL inhibited high glucose-induced mesothelial-to-mesenchymal transition (MMT), as indicated by a reduced expression of fibrosis markers (fibronectin, collagen I, and α-SMA) and increased expression of the epithelial marker E-cadherin. PTL also significantly decreased TGF-β1 expression and the phosphorylation of IκBα and NF-κBp65. The changes in the levels of TGF-β1 expression and p-p65 or p65 showed similar trends according to western blot, immunohistochemistry, and immunofluorescence assays in vitro and in vivo. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were used to confirm that PTL regulates the transcription of TGF-β1 induced by high glucose through NF-κBp65. In summary, PTL induces a therapeutic effect in peritoneal fibrosis by inhibiting inflammation via the NF-κB/ TGF-β/Smad signaling axis.

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Fig. 1: Cytotoxic effects of different concentrations (0, 83, 138, 256 mM) of glucose on HMrSV5 cells after 48-h exposure as measured by MTT assay.
Fig. 2: PTL alleviates inflammation in peritoneal fibrosis in vitro and in vivo.
Fig. 3: PTL inhibits high glucose-induced MMT in HMrSV5 cells.
Fig. 4: PTL inhibits high glucose-induced MMT in RPMCs.
Fig. 5: PTL decreases the expression of TGF-β1 by inhibiting the NF-κB signaling pathway in a mouse model of PD.
Fig. 6: PTL decreases the expression of TGF-β1 by inhibiting the NF-κB signaling pathway in vitro.
Fig. 7: PTL regulates the transcription of TGF-β1 induced by high glucose through NF-κBp65.

Data availability

The data used to support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We would like to thank Professor Xueqing Yu for providing the HMrSV5 cells, Accendatech Co., Ltd. (Tianjin, China) for providing PTL, and Central Laboratory in the Second Affiliated Hospital of Guangzhou Medical University for providing experimental sites.

Funding

We acknowledge the financial support provided by the Medical Scientific Research Foundation of Guangdong Province, China (No. A2021398), the Basic and Applied Basic Research Foundation of Guangdong Province, China (No. 2022A1515012665), the National Natural Science Foundation of China (NSFC) (no. 81800612), the Natural Science Foundation of Guangdong Province, China (No. 2020A1515011295), University Scientific Research Project of Guangzhou Education Bureau (No. 201831833).

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JL, HL, and YH performed study concept and design; YZ, WF, XP, and LZ performed development of methodology and writing, review, and revision of the paper; ZW, HS, CC, LX, YZ, and ML provided acquisition, analysis and interpretation of data, and statistical analysis; YZ, XP, and SL provided technical and material support. All authors read and approved the final paper.

Corresponding authors

Correspondence to Ying Huang, Haibo Long or Jianbo Liang.

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All experimental procedures were approved by the second Affiliated Hospital of Guangzhou Medical University. The studies were performed in accordance with the Declaration of Helsinki and to the Guide for the Care and Use of Laboratory Animals designated by the National Research Council.

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Zhang, Y., Feng, W., Peng, X. et al. Parthenolide alleviates peritoneal fibrosis by inhibiting inflammation via the NF-κB/ TGF-β/Smad signaling axis. Lab Invest 102, 1346–1354 (2022). https://doi.org/10.1038/s41374-022-00834-3

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