A Network Pharmacology Approach to Explore the Mechanism of HuangZhi YiShen Capsule for Treatment of Diabetic Kidney Disease

Abstract

Background and objective: HuangZhi YiShen Capsule (HZYS) is a Chinese patent herbal drug that protects kidney function in diabetic kidney disease (DKD) patients. However, the pharmacologic mechanisms of HZYS remain unclear. This study would use network pharmacology to explore the pharmacologic mechanisms of HZYS.

Methods: Chemical constituents of HZYS were obtained through the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) and literature search. Potential targets of HZYS were identified by using the TCMSP and the SwissTarget Prediction databases. DKD-related target genes were collected by using the Online Mendelian Inheritance in Man, Therapeutic Target Database, GeneCards, DisGeNET, and Drugbank databases. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were carried out to further explore the mechanisms of HZYS in treating DKD. Molecular docking was conducted to verify the potential interactions between the prime compounds and the hub genes.

Results: 179 active compounds and 620 target genes were obtained, and 571 common targets were considered potential therapeutic targets. The top 10 main active compounds of HZYS were heparin, quercetin, kaempferol, luteolin, methyl14-methylpentadecanoate, methyl (Z)-11-hexadecenoate, 17-hydroxycorticosterone, 4-pregnene-17α, 20β, 21-triol-3, 11-dione, wogonin, and hydroxyecdysone. Hub signaling pathways by which HZYS treating DKD were PI3K-Akt, MAPK, AGE-RAGE in diabetic complications, TNF, and apoptosis. The top 10 target genes associated with these pathways were IL6, MAPK1, AKT1, RELA, BCL2, JUN, MAPK3, MAP2K1, CASP3, and TNF. Quercetin and Luteolin were verified to have good binding capability with the hub potential targets IL6, MAPK1, AKT1 through molecular docking.

Conclusion: HZYS appeared to treat DKD by regulating the inflammatory, oxidative stress, apoptotic, and fibrosis signaling pathways. This study provided a novel perspective for further research of HZYS.

Keywords: HuangZhi YiShen Capsule; diabetic kidney disease; molecular docking; network pharmacology.

Figure 1

Schema of network pharmacology analysis of HZYS.

Figure 2

Matching of target genes between DKD and HZYS.

Figure 3

Visual analysis of herb-compound-disease-common target network. Green diamonds represent the targets; purple Vs represent the calculated ingredients; light green triangles represent the calculated drugs. The size and color of the border are arranged according to the degree value. (DKD: diabetic kidney disease; HZYS: Huangzhi Yishen capsule.)

Figure 4

Common target PPI network between DKD and HZYS.

Figure 5

Bar plot of 30 core targets that have more connection nodes based on the PPI network. The number of each bar represents the number of connection nodes associated with the target.

Figure 6

GO enrichment of biologic process (BP) of potential targets of the main active ingredients in HZYS. The top 30 biologic process are shown in this figure. The abscissa is the adjusted P-value, the larger the value, the smaller the P-value.

Figure 7

GO enrichment of molecular function (MF) of potential targets of the main active ingredients in HZYS. The top 30 terms were shown in this figure. The abscissa is the adjusted P-value, the larger the value, the smaller the P-value.

Figure 8

GO enrichment of the cell component (CC) of potential targets of the main active ingredients in HZYS. The top 30 terms were shown in this figure. The abscissa is the adjusted P-value, the larger the value, the smaller the P-value.

Figure 9

GO enrichment (from R) of potential targets of the main active ingredients in HZYS. Xs represent the number of genes, Ys represent the adjusted P-value. Color of the bar is shown in a gradient from red to blue based on ascending P-value. The top 20 terms are shown in this figure.

Figure 10

KEGG enrichment (from R) of potential targets of the main active ingredients in HZYS. Xs represent the gene ratios, Ys represent the adjusted P-value. The color of the bubble is shown in a gradient from red to blue based on ascending P-value. Size of the bubble is based on the number of genes. The top 20 terms are shown in this figure.

Figure 11

Visual analysis of compound-pathway-target network. Green diamonds represent the targets; blue octagons represent the calculated compounds; red rectangles represent the calculated pathways. The size and color of the border are arranged according to the degree value.

Figure 12

Molecular docking of compound-hub genes. (A) 1ALU to Quercetin (Binding energy = −7.68, Ki = 2.33 μmol/L); (B) 6SLG to Luteolin (Binding energy = −6.32, Ki = 23.31 μmol/L); (C) 4ZZN to Quercetin (Binding energy = −6.78, Ki = 10.74 μmol/L); (D) 1UNQ to Quercetin (Binding energy = −5.82, Ki = 54.16 μmol/L); (1ALU is a crystal structure of IL6; 6SLG is a crystal structure of MAPK1; 4ZZN is a crystal structure of MAPK1; 1UNQ is a crystal structure of AKT1. Interacting amino acids and compound structures are shown in lines, in which amino acids are shown in green, compound structures are shown in pink.)