Abstract
BACKGROUND: A significant cause of advanced renal failure is diabetic nephropathy (DKD), with few treatment options available. Calcitriol shows potential in addressing fibrosis related to DKD, though its molecular mechanisms remain poorly understood. This research seeks to pinpoint the crucial genes and pathways influenced by calcitriol within the scope of DKD-related fibrosis. METHODS: Single-cell gene expression profiling of calcitriol treated DKD rat kidney tissue and screening of fibrosis-associated cell subsets. Mendelian randomization and enrichment analyses (CIBERSORT, GSVA, GSEA, Motif Enrichment) were used to explore gene-immune cell interactions and signaling pathways. Key findings were validated using independent datasets and protein expression data from the Human Protein Atlas. RESULTS: Calcitriol treatment reduced proliferative cell populations and highlighted the FoxO signaling pathway's role in DKD. SUMO3 and CD74 were identified as key markers linked to immune infiltration and renal function. These genes were significantly associated with creatinine levels and eGFR, indicating their potential role in DKD progression. CONCLUSION: Our results suggest that calcitriol modulates DKD fibrosis through the FoxO pathway, with SUMO3 and CD74 serving as potential biomarkers for kidney protection. These results provide fresh insights into strategies for treating DKD.