Aging-related CD8⁺ T cell alterations and calcium/calmodulin dependent protein kinase 1D activation in the pathogenesis of diabetic kidney disease

BACKGROUND: Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease (ESRD), accelerates age-related decline in estimated glomerular filtration rate (eGFR), leading to a markedly increased prevalence of DKD among elderly diabetic patients. Recent studies suggest that immune dysregulation plays a pivotal role in DKD progression; however, the cellular and molecular mechanisms linking aging, immune infiltration, and DKD remain unclear. METHODS: We used single-cell RNA sequencing (scRNA-seq) analysis to characterize immune cell dynamics between the young, the elderly and DKD patients. Based on the scRNA-seq analysis, Mendelian randomization (MR) analysis of differentially expressed genes (DEGs) in CD8⁺ T cells were conducted to explore the casual relationship between DEGs and DKD. RESULTS: The CD8⁺ T cell cluster was the predominant T cell subtype, but its proportion gradually declined from young individuals to elderly subjects and DKD patients. MR analysis of DEGs in CD8⁺ T cells suggested that calcium/calmodulin dependent protein kinase 1D (CAMK1D) exhibited strongest causal relationship with DKD. CAMK1D was upregulated in DKD kidney tissues, and its expression was localized to CD8⁺ T cells, as confirmed by immunofluorescence staining. Functional analysis indicated that CAMK1D⁺ CD8⁺ T cells engaged in pro-inflammatory and pro-fibrotic signaling with various renal cell types and showed enrichment in metabolic pathways related to DKD. CONCLUSION: Our results highlighted the important role of CD8⁺ T cell in shaping the renal immune microenvironment in both DKD and aging. CAMK1D may serve as a shared molecular risk factor linking aging and diabetic renal injury.