Unveiling the Role of Calcium Dobesilate's based on Multi-omics in Combatting Type 1 Diabetic Nephropathy

Background: Diabetic nephropathy seriously endangers patients' lives and imposes a heavy economic burden on the country. Its molecular mechanism and therapeutic targets are not yet fully understood. A deeper understanding of the molecular mechanism of diabetic nephropathy is conducive to slowing down the disease progression and developing new strategies to reduce the risk of end-stage renal disease. Calcium dobesilate (CaD) has a vascular protective effect, but its systemic mechanism in type 1 diabetic nephropathy (T1DKD) has not yet been studied through multi-omics integration. Methods: We conducted transcriptomic, proteomic, and metabolomic profiling, using renal tissues obtained from rats from three groups (NC: non-diabetic; T1DKD: type-1 diabetic kidney disease; AS: CaD-treated T1DKD). Differential expression analysis, pathway enrichment (GO/KEGG/Reactome), and multi-omics integration (nine-quadrant plots, hierarchical clustering, correlation networks) were employed to dissect disease mechanisms and drug effects. Results: Transcriptomics identified 2,301 differentially expressed genes (DEGs) in T1DKD vs NC, enriched in extracellular matrix organization and ECM–receptor interaction, and cell adhesion (NES = -1.841, P <0.01). 214 DEGs were identified in AS vs T1DKD, enriched in immune-inflammatory pathways, activation of the renin-angiotensin system, and extracellular space (NES=1.681, P <0.01). CaD reversed 73 DEGs, involved in tryptophan metabolism and steroid biosynthesis. Proteomics validated 154 Differentially abundant proteins (DAPs) in T1DKD vs NC, linked to immune response activation and RAS hyperactivity, while CaD modulated 14 DAPs involved in innate immune system regulation. CaD reversed 2 DAPs involved in the upregulation of P2RX7 protein. Metabolomics highlighted Pyrimidine metabolism and Vitamin B6 metabolism. Nine-quadrant analysis revealed CaD-driven restoration of steroid biosynthesis ( Cyp27b1 ) and tryptophan metabolism ( Aadat , Cat ). P2RX7 emerged as a calcium signaling hub, negatively correlating with Taurine. Conclusion: Our study delineates systemic molecular disruptions in T1DKD and establishes CaD as a multi-target therapeutic agent that restores metabolic homeostasis and mitigates renal injury through coordinated regulation of tryptophan, and steroid pathway. These findings provide a mechanistic foundation for repurposing CaD in T1DKD management.