Investigation of the Potential Pharmacological Substance Basis and Mechanism of Action of Xuantu Granules in Treating Diabetic Kidney Disease Based on UHPLC-Q-Exactive-HRMS and Bioinformatics

Objective: The objective of this study is to analyze and identify the main chemical components and blood-absorbed components of Xuantu Granules and predict their pharmacological substance basis and mechanism in the treatment of DKD.

Methods: A DKD rat model was established by feeding SD rats a high-fat and high-sugar diet and administering intraperitoneal injections of streptozotocin (STZ). The therapeutic effect of Xuantu granules was evaluated. Drug-containing serum was prepared after gavage, and the major chemical components of Xuantu Granules and the drug-containing serum were detected using UHPLC-Q-Exactive-HRMS. Blood-absorbed components were identified based on retention time, mass-to-charge ratio, and MS/MS spectrum. Blood-absorbed components' target proteins were searched using the CTD, SwissTarget, BindingDB, and TargetNet databases. DKD disease target genes were screened from the GEO database using WGCNA. A "bioactive blood-absorbed component-target-disease" PPI network was constructed using Cytoscape software, and the key clustering subnetworks were identified by MCODE plugin. GO functional analysis and KEGG pathway enrichment analysis were performed on subnetworks.

Results: Xuantu Granules lowered fasting blood glucose, improved renal function, reduced proteinuria, and improved renal tissue pathological changes in DKD rats. 36 chemical components were identified, among which 12 compounds, including β -Carboline-1-propionic acid, Morin, Afzelin, Schizandrin, Gomisin A were identified as blood-absorbed components. Bioinformatics analysis indicated that AKT1, TNF, TP53, IL6, SRC, IL1B, EGFR, JUN, BCL2, and CASP3 might be the main therapeutic targets. The involved pathways included the IL-17 signaling pathway, PI3K-Akt signaling pathway, AGE-RAGE signaling pathway in diabetic complications and so on.

Conclusion: Xuantu Granules may exert therapeutic effects on DKD through multiple targets and pathways.