Exploring New Therapeutic Directions for Diabetic Kidney Disease Using High-Throughput Sequencing

Abstract

Objective: To screen for miRNAs and mRNAs with target‑binding relationships, DKD‑related signaling pathways, and potential therapeutic agents for diabetic kidney disease (DKD), so as to explore novel therapeutic directions for DKD at the gene, signaling pathway, and drug levels. Methods: Differential miRNAs and mRNAs associated with DKD were screened from high‑throughput sequencing datasets downloaded from the GEO database using R. The TargetScan database was used to further filter miRNAs and mRNAs with target‑binding interactions. The DSigDB database was employed to identify drug components targeting proteins encoded by differentially expressed mRNAs, and molecular docking was performed to validate their binding stability. Results: In total, 17 miRNAs with >4‑fold change, 68 mRNAs with >2‑fold change, and 7 mRNAs with >4‑fold change were retrieved from the GEO database. KEGG enrichment analysis revealed several key DKD‑associated signaling pathways, including the IL‑17, NF‑κB, TGF‑β, and TNF signaling pathways. TargetScan further identified 7 miRNAs and 26 mRNAs with reciprocal target‑binding interactions. Using DSigDB, 51 drug components with potential therapeutic effects against DKD (e.g., acetovanillone, ademetionine, beta‑carotene, pterostilbene) and their five corresponding target proteins OLR1, IL1B, SERPINB2, CXCL3, and ALAS2 were identified. Molecular docking confirmed stable binding between these drug components and their target proteins. Conclusion: Hsa-miR-142-5p, hsa-miR-1225-3p, hsa-miR-513a-5p, along with mRNAs encoding OLR1, IL1B and ALAS2, may serve as key targets for DKD prevention and treatment. The IL‑17, NF‑κB, TGF‑β, and TNF signaling pathways exert critical regulatory functions during DKD pathogenesis and represent core pathways for therapeutic intervention. Moreover, natural active compounds including acetovanillone, ademetionine, beta‑carotene, and pterostilbene exhibit promising therapeutic potential for DKD. These findings provide a theoretical basis and novel insights for exploring DKD pathogenesis and developing targeted preventive and therapeutic strategies, and help improve clinical prognosis and slow DKD progression in patients.