Potential Molecular Mechanism of Yishen Capsule in the Treatment of Diabetic Nephropathy Based on Network Pharmacology and Molecular Docking

Abstract

Purpose

Using network pharmacology and molecular docking to explore the mechanism of Yishen Capsule in the treatment of diabetic nephropathy.

Materials and Methods

Active components of Yishen Capsule were obtained using database such as TCMSP and TCMID. UniProt protein database was used to screen and standardize the human-derived targets of the active chemical components. Diabetic nephropathy (DN) targets were obtained from databases such as GeneCards, OMIM, TTD, DisGeNET and DrugBank. A network of “Yishen Capsule Components-diabetic nephropathy Targets-Pathways” was constructed by analyzing data above to screening out core targets for molecular docking verification. DN is induced by streptozocin in rats after left nephrectomy. Renal tubular epithelial cells (RTECs) was isolated  and cultured under high glucose conditions. Based on these experimental models, key pathway target genes screened by network pharmacology were verified both in vitro and in vivo.

Results

The main active components of Yishen Capsule in the treatment of DN include quercetin, kaempferol, gallic acid, astragaloside IV, etc. Some key targets (such as AR, AKT1, TP53, ESR1, JUN) and important signal pathways (such as AGE-RAGE, HIF-1 and JAK-STAT signal pathway) were included in the treatment of DN with Yishen Capsule. Molecular docking assay showed that most of the targets have good binding activity with the components of Yishen Capsule. Based on the results of network pharmacology, key target proteins in HIF-1α and JAK2/STAT3 signaling pathways were selected for experimental verification. Results presented that HIF-1α, JAK2, STAT3, TGF-β and MCP-1 were increased under high glucose environment. With the treatment of Yishen Capsule, the expression of HIF-1α further increased, while the expression of JAK2, STAT3, MCP-1 and TGF-β was decreased.

Conclusion

This study revealed the mechanism of Yishen Capsule in the treatment of DN, which possesses the characteristics of multi-component, multi-target, and multi-pathway. Further experiments confirmed that Yishen Capsule interfered with HIF-1α and JAK/STAT signaling pathways to reduce inflammation and fibrosis damage in the kidney tissue of rats with diabetic nephropathy.

Keywords:

• diabetic nephropathy
• network pharmacology
• molecular docking
• HIF-1α
• JAK/STAT

Acknowledgments

Thanks to all project participants for their dedication to this research.

Author Contributions

YLH and SL conducted bioinformatics data analysis. YLH, ZYZ, and SFL conducted in vivo experiments. YXL and DLS conducted in vitro experiments. YLH, ZYZ, and YXL conducted molecular biological analysis. YLH and SL prepared the manuscript. WYL, GZ and JAF conceptualized this research and finalized this manuscript. All authors contributed to data analysis, drafting or revising the article, have agreed on the journal to which the article will be submitted, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.

Additional information

Funding

This study has been supported by the National Natural Science Foundation of China [81873159], Shanxi Key Research and Development Project (International Science and Technology Cooperation) [No. 201903D421057], Shanxi Applied Basic Research Project (Natural Science Foundation Project) [No. 201801D121341], Scientific research project [No. 2018040, No. 2017040] funded by Health and Family Planning Commission of Shanxi Province.