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Journal of Traditional Chinese Medicine >

2024 , Vol. 44 >Issue 2: 362 - 372

DOI: https://doi.org/10.19852/j.cnki.jtcm.20230630.003

Network pharmacology and experimental validation to reveal the pharmacological mechanisms of Sini decoction (四逆汤) against renal fibrosis

  • Yan WANG ,
  • Fanying DENG ,
  • Shiqi LIU ,
  • Yingli WANG
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  • 1 Department of Pharmacy, Shanxi University of Chinese Medicine, Jinzhong 030619, China
    2 Schools of Basic Medical Sciences, Heilongjiang University of Chinese Medicine, Haerbin 150040, China

Received date: 2022-12-22

  Accepted date: 2023-04-08

  Online published: 2023-06-30

Supported by

National Natural Science Foundation of China: General Program: Research on the Protective Effect of Component Wu Sini Decoction on Hypothyroidism and Kidney Injury and Its Mechanism of Action(81373546);Study on the Protective Effect and Mechanism of Wu Sini decoction on Renal Fibrosis(2016021165);Shanxi University of Chinese Medicine Pharmacology Discipline Construction Project(2023XKJS-25);Shanxi University of Chinese Medicine Pharmacy Discipline Construction Project(2023XKJS-26)

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Abstract

OBJECTIVE: To investigate the mechanism by which Sini decoction (四逆汤, SND) improves renal fibrosis (Rf) in rats based on transforming growth factor β1/Smad (TGF-β1/Smad) signaling pathway.

METHODS: Network pharmacology was applied to obtain potentially involved signaling pathways in SND's improving effects on Rf. The targets of SND drug components and the targets of Rf were obtained by searching databases, such as the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCSMP) and GeenCard. The intersection targets of two searches were obtained and underwent signaling pathway analysis using a Venn diagram. Then experimental pharmacology was utilized to prove and investigate the effects of SND on target proteins in the TGF-β1/Smad signaling pathway. The Rf rat model was established by unilateral ureteral occlusion (UUO). The expression levels of transforming growth factor, matrix metalloproteinase-9 (MMP-9), matrix metal protease-2 (MMP-2), connective tissue growth factor (CTGF), and tissue inhibitor of metalloproteinase-1 (TIMP-1) were determined by Masson staining of rat renal tissue, and immunohistochemical methods. The expression levels of Smad3, Smad2, and Smad7 in renal tissue were determined by Western blotting (WB). The mechanism of the improving effects of SND on Rf was investigated based on TGF-β1/Smad signaling pathway.

RESULTS: A total of 12 drug components of Fuzi (Radix Aconiti Lateralis Preparata), 5 drug components of Ganjiang (Rhizoma Zingiber), and 9 drug components of Gancao (Radix Glycy et Rhizoma) were obtained from the database search, and 207 shared targets were found. A total of 1063 Rf targets were found in the database search. According to the Venn diagram, in total, 96 intersection targets were found in two database searches. The metabolic pathways involved included TGF-β signaling pathway, phosphatidylinositol-3-kinase/serine-threonine protein kinase signaling (PI3K/Akt) pathway, and hypoxia-inducible factor-1 (HIF-1) signaling pathway. Masson staining analysis showed that compared with the model group, the renal interstitial collagen deposition levels in the SSN and SND groups were significantly lower (P < 0.05). Immunohistochemical analysis, compared with the control group, the positive cell area expression levels of MMP-9/TIMP-1 and MMP-2/TIMP-1 in the kidney tissue of the model group were significantly decreased (P < 0.05, P < 0.01), and the positive cell area expression levels of CTGF and TGF-β1 were significantly increased (P < 0.01). Compared with the model group, the positive cell area expression levels of MMP-9/TIMP-1 and MMP-2/TIMP-1 in the kidney tissue of the SSN and SND groups were significantly increased (P < 0.05, P < 0.01), and the positive cell area expression levels of CTGF and TGF-β1 in the kidney tissue were significantly decreased (P < 0.05, P < 0.01). WB results showed that the SSN group and the SND group could reduce the expression of Smad2 and Smad3 (P < 0.05) and increase the expression of Smad7 (P < 0.05).

Key words： renal fibrosis; network pharmacology; transforming growth factor beta1; smad proteins; Sini decoction

Cite this article

Yan WANG , Fanying DENG , Shiqi LIU , Yingli WANG . Network pharmacology and experimental validation to reveal the pharmacological mechanisms of Sini decoction (四逆汤) against renal fibrosis[J]. Journal of Traditional Chinese Medicine, 2024 , 44(2) : 362 -372 . DOI: 10.19852/j.cnki.jtcm.20230630.003

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