Objective To investigate the gene expression characteristics of renal cortex in diabetic mice treated with astragaloside Ⅳ, and preliminarily screen the potential molecular targets and regulatory pathways underlying its renal protective effect. Methods The db/db mice were randomly divided into an astragaloside Ⅳ intervention group (group A) and a type 2 diabetes mellitus group (group B), with 3 mice in each group. Mice in group A received gavage administration of astragaloside Ⅳ at a dose of 20 mg/kg once daily, while group B received an equal volume of normal saline by the same gavage route. The intervention was continued for 8 consecutive weeks. After the intervention, the body weight of mice in each group was recorded. Fasting blood glucose was measured with a blood glucose meter, and serum urea nitrogen and serum creatinine levels were detected using kits. The renal cortex was isolated for RNA extraction and quality assessment, followed by analysis of differentially expressed genes. The differentially expressed genes were subjected to gene ontology (GO) enrichment analysis, kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis, gene set enrichment analysis (GSEA) and transcription factor target prediction. Results Compared with group B, the levels of fasting blood glucose, serum urea nitrogen and serum creatinine in group A were lower (P<0.05). A total of 949 differentially expressed genes were identified, including 590 upregulated genes and 359 downregulated genes. GO enrichment analysis showed that the upregulated differentially expressed genes were mainly involved in biological processes such as immune response, immune system process and extracellular matrix organization, enriched in cellular components such as collagen trimer, extracellular matrix and plasma membrane, and associated with molecular functions such as transmembrane transporter activity, structural constituent of extracellular matrix and structural constituent of major histocompatibility complex class Ⅱ protein complex. The downregulated differentially expressed genes were mainly involved in biological processes such as circadian rhythm, lipid metabolism, arachidonic acid metabolism and vitamin D metabolism, enriched in cellular components such as endoplasmic reticulum, external side of apical plasma membrane and extracellular region, and associated with molecular functions such as oxidoreductase activity, fatty acid binding and heme/iron ion binding. KEGG enrichment analysis showed that the upregulated differentially expressed genes were enriched in signaling pathways such as phagosome, cell adhesion molecules, and extracellular matrix-receptor interaction, while the downregulated differentially expressed genes were enriched in signaling pathways including retinol metabolism, glutathione metabolism, bile secretion, and circadian rhythm. GSEA results showed that the extracellular matrix-receptor interaction pathway, hematopoietic cell lineage pathway, protein digestion and absorption pathway, and calcium reabsorption pathway regulated by endocrine and other factors were significantly positively enriched. Transcription factor prediction results indicated that transcription factors including THR-like, TF_bZIP, ESR-like, NGFIB-like and IRF were associated with a large number of differentially expressed genes. Conclusion Astragaloside Ⅳ can alter the transcriptomic expression profiles of the renal cortex in diabetic mice, and its effect may be related to inflammatory and immune regulation, extracellular matrix remodeling and improvement of metabolic homeostasis, which provides an experimental basis for elucidating the molecular mechanism of astragaloside Ⅳ in ameliorating diabetic renal injury.

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