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

CD8+ T cells were the predominant T cell subtype but their proportion gradually declined from young individuals to elderly subjects and DKD patients.

• Single-cell RNA sequencing (scRNA-seq) analysis was used to characterize immune cell dynamics between young, elderly, and DKD patients.
• The CD8+ T cell cluster was identified as the predominant T cell subtype across all groups.
• A progressive reduction in CD8+ T cell proportion was observed across the aging-to-DKD continuum.
• The analysis characterized immune cell dynamics across three distinct groups: young individuals, elderly subjects, and DKD patients.

Mendelian randomization analysis identified CAMK1D as having the strongest causal relationship with DKD among differentially expressed genes in CD8+ T cells.

• MR analysis was conducted on differentially expressed genes (DEGs) in CD8+ T cells to explore causal relationships with DKD.
• CAMK1D (calcium/calmodulin dependent protein kinase 1D) showed the strongest causal relationship with DKD among all DEGs analyzed.
• The MR approach was used to infer causality rather than mere association between CD8+ T cell gene expression and DKD.

CAMK1D was upregulated in DKD kidney tissues and its expression was localized to CD8+ T cells.

• CAMK1D upregulation in DKD kidney tissues was identified through analysis of kidney tissue data.
• Immunofluorescence staining confirmed that CAMK1D expression was localized to CD8+ T cells in kidney tissue.
• The co-localization of CAMK1D with CD8+ T cells was validated as a confirmatory step following the computational findings.

CAMK1D+ CD8+ T cells engaged in pro-inflammatory and pro-fibrotic signaling with various renal cell types.

• Functional analysis of CAMK1D+ CD8+ T cells revealed engagement in pro-inflammatory signaling pathways.
• CAMK1D+ CD8+ T cells also showed pro-fibrotic signaling interactions with various renal cell types.
• CAMK1D+ CD8+ T cells showed enrichment in metabolic pathways related to DKD.
• These findings suggest CAMK1D+ CD8+ T cells actively shape the renal immune microenvironment in DKD.

CD8+ T cells play an important role in shaping the renal immune microenvironment in both DKD and aging.

• The study characterized immune cell dynamics using scRNA-seq across young, elderly, and DKD patient groups.
• The results highlighted that CD8+ T cell alterations are relevant to both aging-related and DKD-related renal changes.
• CAMK1D was proposed as a shared molecular risk factor linking aging and diabetic renal injury.
• Immune dysregulation, particularly involving CD8+ T cells, was identified as playing a pivotal role in DKD progression.