Abstract
Background Diabetic kidney disease (DKD) poses a major public-health burden globally. Tripterygium wilfordii Hook F (TwHF) is a widely employed herbal medicine in decreasing albuminuria among diabetic patients. However, a holistic network pharmacology strategy to investigate the active components and therapeutic mechanism underlying DKD is still unavailable. Methods We collected TwHF ingredients and their targets by traditional Chinese Medicine databases (TCMSP). Then, we obtained DKD targets from GeneCards and OMIM and collected and analyzed TwHF-DKD common targets using the STRING database. Protein-protein interaction (PPI) network was established by Cytoscape and analyzed by MCODE plugin to get clusters. In addition, the cytoHubba software was used to identify hub genes. Finally, all the targets of clusters were subjected for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses via DAVID. Results A total of 51 active ingredients in TwHF were identified and hit by 88 potential targets related to DKD. Compounds correspond to more targets include kaempferol, beta-sitosterol, stigmasterol, and Triptoditerpenic acid B, which appeared to be high-potential compounds. Genes with higher degree including VEGFA, PTGS2, JUN, MAPK8, and HSP90AA1 are hub genes of TwHF against DKD, which are involved in inflammation, insulin resistance, and lipid homeostasis. Kaempferol and VEGFA were represented as the uppermost active ingredient and core gene of TwHF in treating DKD, respectively. DAVID results indicated that TwHF may play a role in treating DKD through AGE-RAGE signaling pathway, IL-17 signaling pathway, TNF signaling pathway, insulin resistance, and calcium signaling pathway (P < 0.05). Conclusion Kaempferol and VEGFA were represented as the uppermost active ingredient and core gene of TwHF in treating DKD, respectively. The key mechanisms of TwHF against DKD might be involved in the reduction of renal inflammation by downregulating VEGFA.
Highlights
Diabetic kidney disease (DKD), a highly prevalent microvascular complication of diabetes, is characterized by thickening of the glomerular basement membrane, mesangial expansion, podocyte, and glomerular injury, leading to glomerular sclerosis and tubulointerstitial fibrosis [1]
By mapping 51 compounds linked to 93 targets, the network consists of 126 nodes and 579 edges, in which the components calculated in yellow from Tripterygium wilfordii Hook F (TwHF), and the colorized pink circles reflect cotarget genes of TwHF-DKD, and red circles stand for component targets only
Our research indicated that TwHF might modulate lipid homeostasis and insulin resistance under diabetic environment, which provided a novel explanation for elucidating the potential mechanisms of TwHF on DKD, but our hypotheses need further experimental validation
Summary
Diabetic kidney disease (DKD), a highly prevalent microvascular complication of diabetes, is characterized by thickening of the glomerular basement membrane, mesangial expansion, podocyte, and glomerular injury, leading to glomerular sclerosis and tubulointerstitial fibrosis [1] It occurs in almost 20-50% patients with type 1 or type 2 diabetes worldwide, and even in the presence of adequate glycemic control, it remains the main cause of morbidity and mortality among diabetic patients [2, 3]. Current standard therapies to manage DKD recommend drugs controlling blood pressure and hyperglycemia, mainly including renin angiotensin aldosterone system (RAAS) inhibitors, sodium glucose cotransporter 2 (SGLT2) inhibitors, and glucagon-like peptide 1 (GLP1) receptor agonist Despite those strategies showing promising results in DKD, many diabetic patients continue to progress to DKD and ESKD [3, 4].
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