A bioinformatics and network pharmacology approach to the mechanisms of action of Shenxiao decoction for the treatment of diabetic nephropathy

Xin Mou; Di Yi Zhou; Danyang Zhou; Kaiyuan Liu; Li Jun Chen; Wen Hong Liu

doi:10.1016/j.phymed.2020.153192

A bioinformatics and network pharmacology approach to the mechanisms of action of Shenxiao decoction for the treatment of diabetic nephropathy

Phytomedicine. 2020 Apr:69:153192. doi: 10.1016/j.phymed.2020.153192. Epub 2020 Feb 22.

Authors

Xin Mou¹, Di Yi Zhou¹, Danyang Zhou¹, Kaiyuan Liu¹, Li Jun Chen¹, Wen Hong Liu²

Affiliations

¹ Department of Endocrinology, Zhejiang Integrated and Western Medicine Hospital, Hangzhou, Zhejiang 310003, PR China.
² Zhejiang Chinese Medical University, 548 Binwen Road, Binjiang, Hangzhou, Zhejiang 310053, PR China. Electronic address: lwh687@163.com.

PMID: 32200292
DOI: 10.1016/j.phymed.2020.153192

Abstract

Background: The epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells is the main pathological alteration in diabetic nephropathy (DN). Traditional Chinese medicine (TCM) has been used for the treatment of DN in clinical practice and has been proven to be effective.

Purpose: This aim of this study was to shed light on the efficacy of Shenxiao decoction (SXD) on the EMT of renal tubular epithelial cells and the molecular mechanisms of SXD in mice with DN, as well as on the high glucose (HG)- and TGF-β1-induced EMT of NRK-52E and HK-2 cells.

Study design and methods: A bioinformatics and network pharmacology method were utilized to construct the active ingredient-target networks of SXD that were responsible for the beneficial effects against DN. The effects of RUNX3 were validated in HG- and TGF-β1-induced EMT processes in NRK-52E and HK-2 cells.

Results: Bioinformatics analysis revealed that 122 matching targets were closely associated with the regulation of cell migration and the AGE-RAGE signaling pathway in diabetic complications. The results also revealed that, relative to the mice with DN, the mice in the treatment group had an improved general state and reduced blood glucose levels. The degradation of renal function was ameliorated by SXD. Moreover, the protective effects of SXD were also observed on renal structural changes. Furthermore, SXD suppressed the activation of the transforming growth factor (TGF)-β1/Smad pathway and upregulated the RUNX3 and E-cadherin levels and downregulated the extracellular matrix (ECM) protein levels in mice with DN. SXD was further found to prevent the HG- and TGF-β1-induced EMT processes in NRK-52E and HK-2 cells. Additionally, the overexpression of RUNX3 markedly inhibited the EMT and TGF-β1/Smad pathway induced by HG and TGF-β1 in NRK-52E and HK-2 cells.

Conclusion: Taken together, these results suggest that SXD maybe alleviate EMT in DN via the inhibition of the TGF-β1/Smad/RUNX3 signaling pathway under hyperglycemic conditions.

Keywords: Bioinformatics and network pharmacology; Diabetic nephropathy; Epithelial-to-mesenchymal transition; RUNX3; Shenxiao decoction.

MeSH terms

Animals
Computational Biology / methods*
Core Binding Factor Alpha 3 Subunit / genetics
Core Binding Factor Alpha 3 Subunit / metabolism
Diabetes Mellitus, Experimental / complications
Diabetic Nephropathies / drug therapy*
Diabetic Nephropathies / genetics
Diabetic Nephropathies / metabolism
Diabetic Nephropathies / pathology
Down-Regulation / drug effects
Drugs, Chinese Herbal / chemistry
Drugs, Chinese Herbal / pharmacology*
Epithelial Cells / drug effects
Epithelial-Mesenchymal Transition / drug effects
Hypoglycemic Agents / pharmacology
Kidney / drug effects
Kidney / pathology
Male
Mice, Inbred C57BL
Protein Interaction Maps
Rats
Smad Proteins / genetics
Smad Proteins / metabolism
Transforming Growth Factor beta / metabolism
Transforming Growth Factor beta / pharmacology
Up-Regulation / drug effects

Substances

Core Binding Factor Alpha 3 Subunit
Drugs, Chinese Herbal
Hypoglycemic Agents
Smad Proteins
Transforming Growth Factor beta