Three significant signaling pathways (hsa04066, hsa04668, hsa04151) were selected as the critical pathways by PPI networks and enrichment analysis of common-targets, which were mainly related to three functional modules including inflammation, apoptosis and angiogenesis. Therefore, this research was focused on these three modules.
It was reported that gynostemma pentaphyllum could remarkably suppress the increase of triglyceride, total cholesterol and LDL-cholesterol in serum caused by high-fat diet . Gao et al found that gynostemma pentaphyllum had the function of hypoglycemic and hypolipidemic by the expression of NFE2-related factor 2 signaling in diabetic rats .
In some previous studies, lipid accumulation in the kidney was considered to be the key process in DKD [33–34]. And a research reported that quercetin could alleviate lipid accumulation in the kidney of DKD rats by regulating the expression of sterol regulatory element-binding proteins (SREBPs) and LDL receptor protein, which were controlled by Akt . In addition, quercetin could also regulate the expression of insulin receptor substrate and glucokinase and improved the insulin secretion function of β-cells . In terms of blood lipid, a study showed that 1% quercetin diet could reduce the content of FFA in serum of rats and promoted the catabolism of fat .
Gypenosides could significantly reduce the insulin resistance parameters and increased the glycogen concentration . As well, gypenosides could effectively prevent hyperlipidemia and atherosclerosis. Some related researches found that theregulation of blood lipid was related to the inhibition of FFA produced by adipocytes and the promotion of neutral fat synthesis [39–40]. Therefore, quercitrin and gypenosides may be key ingredients in the therapy.
The inflammatory model showed that gynostemma pentaphyllum may influence inflammation through HIF-1 signaling pathway and TNF signaling pathway. Pro-inflammatory cytokines IL-6 was the key gene in these two pathways. Senn et al found that IL-6 could inhibit the insulin signal transduction and insulin action . And another study reported that the release of IL-6 could weaken the function of pancreatic β cells, leading to insulin resistance, insulin secretion dysfunction and the occurrence of metabolic syndrome . Therefore, abnormal secretion of IL-6 may result in the hyperlipidemia in DKD by affecting insulin. In addition, a significant inhibition of IL-6 was observed in the gypenosides concentration of 150 µg/ml and 200 µg/ml . It was reasonable to believe that gynostemma pentaphyllum may inhibit the expression of IL-6, which furthermore would relieve the DKD.
Some inflammatory cytokines, such as TNF-α, could activate the NF-κB signaling pathway, which would aggravate the inflammatory response and accelerate the development of DKD . And a significant inhibition of TNF-α was observed in the gypenosides concentration range of 100–200 µg/ml . These results indicated that gynostemma pentaphyllum may inhibit the expression of TNF-α to improve inflammation and lipid metabolism in DKD.
HIF-1 signaling pathway and PI3K-Akt signaling pathway acted as the crucial roles in apoptosis and angiogenesis. And HIF-1α as a transcription factor could stimulate the expression of cytokines related to renal interstitial cell fibrosis, which would aggravate the diabetic kidney injury [45–46]. Some animal studies indicated that HIF could cause the increase of insulin sensitivity as well as the decrease of serum cholesterol levels [47, 48]. The mechanism might be associated with the reduction of metabolite accumulation in glycolysis and TCA cycle in diabetic renal cortical tissue . These results showed that HIF stabilization could ameliorate lipid metabolic abnormalities in DKD. Another study reported that quercetin could scavenge the ROS to reduce the level of HIF-1αand reduce the level of caspase-9 in H2O2-treated cells, suggesting that quercetin could inhibit the caspase-dependent apoptosis . These results showed that gynostemma pentaphyllum could inhibit the cell apoptosis as a HIF stabilizer, which may be related to the mechanism that gynostemma pentaphyllum ameliorated the lipid metabolic abnormalities in DKD.
PI3K and the downstream effector Akt belonged to the signal transduction enzymes and was involved in regulating cellular activation and apoptosis . Li et al  found that the PI3K signaling pathway played a crucial part in autophagy and DKD, of which the mechanism may be related to the podocyte adhesion injury. In terms of tumors, Maurya et al reported that quercetin modulated the PI3K-AKT signaling pathway and reduced the Akt and PDK1 phosphorylation , which was similar to the mechanism that gynostemma pentaphyllum ameliorated lipid metabolic abnormalities in DKD.
VEGF was a growth factor for endothelial cell, which played a crucial part in the process of angiogenesis . VEGFA was closely related to angiogenesis, which was mediated by VEGF receptor 1 (VEGFR1) and VEGFR2 signaling pathways [55–56]. A study found that quercetin can significantly suppress the activation of VEGFR2 downstream molecules, to inhibit angiogenesis, such as AKT and mTOR. Few studies have reported that gynostemma pentaphyllum improved the symptoms of DKD through increasing the angiogenesis, more research is needed to confirm these points in the future.