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Mangiferin alleviates diabetic pulmonary fibrosis in mice via inhibiting endothelial-mesenchymal transition through AMPK/FoxO3/SIRT3 axis

Acta Pharmacologica Sinica volume 45, pages 1002–1018 (2024)Cite this article

Abstract

Diabetes mellitus results in numerous complications. Diabetic pulmonary fibrosis (DPF), a late pulmonary complication of diabetes, has not attracted as much attention as diabetic nephropathy and cardiomyopathy. Mangiferin (MF) is a natural small molecular compound that exhibits a variety of pharmacological effects including anti-inflammatory, anti-cancer, anti-diabetes, and anti-fibrosis effects. In this study, we investigated whether long-term diabetes shock induces DPF, and explored whether MF had a protective effect against DPF. We first examined the lung tissues and sections of 20 diabetic patients obtained from discarded lung surgical resection specimens and found that pulmonary fibrosis mainly accumulated around the pulmonary vessels, accompanied by significantly enhanced endothelial-mesenchymal transition (EndMT). We established a mouse model of DPF by STZ injections. Ten days after the final STZ injection, the mice were administered MF (20, 60 mg/kg, i.g.) every 3 days for 4 weeks, and kept feeding until 16 weeks and euthanized. We showed that pulmonary fibrotic lesions were developed in the diabetic mice, which began around the pulmonary vessels, while MF administration did not affect long-term blood glucose levels, but dose-dependently alleviated diabetes-induced pulmonary fibrosis. In human umbilical vein endothelial cells (HUVECs), exposure to high glucose (33.3 mM) induced EndMT, which was dose-dependently inhibited by treatment with MF (10, 50 μM). Furthermore, MF treatment promoted SIRT3 expression in high glucose-exposed HUVECs by directly binding to AMPK to enhance the activity of FoxO3, which finally reversed diabetes-induced EndMT. We conclude that MF attenuates DPF by inhibiting EndMT through the AMPK/FoxO3/SIRT3 axis. MF could be a potential candidate for the early prevention and treatment of DPF.

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Fig. 1: EndMT was involved in pulmonary perivascular fibrosis in diabetic patients.
Fig. 2: MF inhibited EndMT in STZ-induced DPF in vivo.
Fig. 3: MF inhibited EndMT in high glucose-induced HUVECs in vitro.
Fig. 4: MF attenuated EndMT via activating SIRT3 expression in high glucose-induced HUVECs in vitro.
Fig. 5: MF increased SIRT3 expression via activating the activity of FoxO3 in high glucose-induced HUVECs in vitro.
Fig. 6: MF inhibited EndMT through AMPK/FoxO3/SIRT3 axis in high glucose-induced HUVECs in vitro.
Fig. 7: MF improved SIRT3 expression levels via AMPK/FoxO3 pathway in vivo.
Fig. 8: The possible mechanism by which MF alleviates DPF.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 82102269) and the Fundamental Research Funds for the Central Universities (No. 2042023kf0011).

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  1. These authors contributed equally: Ting-lv Fu, Guo-rui Li, Dong-hang Li

Authors and Affiliations

  1. Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China

    Ting-lv Fu, Guo-rui Li, Dong-hang Li, Ru-yuan He, Bo-hao Liu, Rui Xiong, Chen-zhen Xu, Zi-long Lu, Cong-kuan Song, Wen-jie Wang, Shi-shi Zou, Ke Yi, Ning Li & Qing Geng

  2. Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, 130061, China

    Bo-hao Liu

  3. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China

    Hong-liang Qiu

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Contributions

TLF, GRL, and DHL designed, completed most of experiments, analyzed data, made graphs, and wrote the manuscript. RYH, BHL, RX, SSZ, and KY participated in molecular and cellular biological experiments. CZX and ZLL performed animal studies. WJW, CKS, and HLQ collected clinical information and materials. NL and QG designed experiments and the study, analyzed data, reviewed the data, and reviewed the manuscript.

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Correspondence to Ning Li or Qing Geng.

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Fu, Tl., Li, Gr., Li, Dh. et al. Mangiferin alleviates diabetic pulmonary fibrosis in mice via inhibiting endothelial-mesenchymal transition through AMPK/FoxO3/SIRT3 axis. Acta Pharmacol Sin 45, 1002–1018 (2024). https://doi.org/10.1038/s41401-023-01202-7

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