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  3. Exploring the molecular mechanism of berberine for treating diabetic nephropathy based on network pharmacology

Exploring the molecular mechanism of berberine for treating diabetic nephropathy based on network pharmacology

  • Int Immunopharmacol. 2023 Nov 15:126:111237. doi: 10.1016/j.intimp.2023.111237.
Lin Yang 1,  Siming Yuan 2,  Rongrong Wang 1,  Xiaoyu Guo 1,  Yongsheng Xie 2,  Wei Wei 3,  Liqin Tang 4
Affiliations

Affiliations

  • 1 Institute of Clinical Pharmacology, Key Laboratory of Anti-Infammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Infammatory and Immune Medicine, Shushan District, Anhui Medical University, Hefei, Anhui 230032, China; Department of Pharmacy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China.
  • 2 Department of Pharmacy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China.
  • 3 Institute of Clinical Pharmacology, Key Laboratory of Anti-Infammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Infammatory and Immune Medicine, Shushan District, Anhui Medical University, Hefei, Anhui 230032, China. Electronic address: [email protected].
  • 4 Department of Pharmacy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China. Electronic address: [email protected].
PMID: 37977063 DOI: 10.1016/j.intimp.2023.111237
Abstract

Background and purpose: Diabetic nephropathy (DN) is a prevalent complication of diabetes mellitus characterized by hyperglycemia, hyperlipidemia, albuminuria and edema. Increasing evidence indicated that berberine (BBR) could alleviate the occurrence and development of DN. However, the molecular mechanism underlying the beneficial effects of BBR in the treatment of DN remains unclear.

Methods: The online public databases were chosen to screen the relevant targets of BBR and DN and the screened overlapped targets were analyzed by GO enrichment analysis, KEGG enrichment analysis and protein-protein interaction network analysis. The interaction between BBR and the key proteinwas verified by molecular docking and cellularthermalshiftassay. Additionally, the expression of key proteins and related indicators of DN were verified by immunofluorescence and western blot in vitro and in vivo.

Results: We successfully identified 92 overlapped targets of BBR and DN based on network pharmacology. Notably, VEGFR2/KDR/Flk-1 was identified to be the main target of BBR. Meanwhile, we found that BBR exhibited a high binding affinity to VEGFR2/KDR/Flk-1 protein, as confirmed by molecular docking and CETSA. This binding led to interfering with the PI3K/Akt/mTOR signaling pathway. In addition, we found that BBR could inhibit the abnormal proliferation of mesangial cells and reduce the expression of downstream pathway protein in vitro and in vivo. Finally, BBR was found to effectively lower the level of blood glucose and improve kidney function in mice, highlighting its potential as a therapeutic agent for the treatment of DN.

Conclusion: Berberine interfered the PI3K/Akt/mTOR signaling pathway via targeting VEGFR2/KDR/Flk-1 protein, further led to the inhibition of abnormal proliferation of mesangial cells and ultimately resulted in improved renal function.

Keywords

Berberine; Diabetic nephropathy; Mesangial cells; Network pharmacology; PI3K/AKT/mTOR signaling pathway; VEGFR2.

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