The Link Between Serum Copper and Diabetic Kidney Disease: A Plasma Proteomic Perspective

Diabetic kidney disease (DKD) is a significant microvascular complication of diabetes, accounting for the majority of cases of end-stage renal disease. Copper, an essential trace element, has been identified as a factor closely associated with the onset and progression of DKD. However, the precise causal link between serum copper levels and DKD, along with the mechanisms governing their association, remains unclear.

This study employed Mendelian randomization (MR) analysis based on large-scale GWAS data to explore the causal relationship between serum copper levels and DKD. Additionally, mediation analysis was conducted using plasma proteomic data, complemented by enrichment analysis to explore the mediating metabolic pathways or signaling pathways through which serum copper may mediate the development of DKD.

MR results demonstrated that elevated serum copper levels significantly increased the risk of DKD (OR = 1.123, p < 0.001). Additionally, no evidence of pleiotropy or heterogeneity was detected, which provides further assurance of the reliability of results. Protein mediation analysis identified 10 plasma proteins, including FABP, Netrin-1, and glutathione S-transferase A4 as critical mediators in copper-driven DKD, with mediation effects ranging from 6.42% to 28.02%. Following the identification of these 10 mediator proteins, 11 intermediary pathways that mediated the effect of serum copper levels on the onset of DKD were identified.

This study elucidates the causal effect of copper levels on DKD and reveals the underlying mechanism by which increased serum copper levels lead to the development of DKD, offering novel insights and potential therapeutic targets for DKD prevention and treatment.