Abstract
OBJECTIVE: Cuproptosis, a newly discovered cell death mechanism, has been linked to the pathogenesis of multiple diseases. However, its role in diabetic kidney disease (DKD) remains unclear. METHODS: By analyzing datasets GPL17586 and GPL571 from the GEO database and applying machine learning, cuproptosis-related marker genes associated with DKD were identified. The expression levels of these genes were examined in Mouse Podocyte Cell Line (MPC5) podocytes cultured in vitro and treated with high glucose (30 mM) for 24, 48, and 72 h to explore their roles in the onset and progression of DKD. RESULTS: Key genes in the cuproptosis pathway, integrin β6 (ITGB6) and latent transforming growth factor beta-binding protein 1 (LTBP1), were significantly upregulated in DKD patients. Consistent with this, in high glucose-treated podocytes, the expression of ITGB6 and LTBP1 was significantly higher than in the control group at 24, 48, and 72 h. The area under the receiver operating characteristic (ROC) curve (AUC) for ITGB6 and LTBP1 in both the training set (GPL17586) and validation set (GPL571) exceeded 0.7, indicating good diagnostic efficacy for DKD. Furthermore, immune infiltration analysis further revealed that ITGB6 and LTBP1 were significantly positively correlated with activated B cells, central memory Cluster of Differentiation 4 (CD4) T cells, effector memory CD4 T cells, effector memory Cluster of Differentiation 8 (CD8) T cells, and immature B cells, while showing a significant negative correlation with neutrophils. CONCLUSION: This study suggests that cuproptosis-related genes ITGB6 and LTBP1 may be associated with the progression of DKD through their potential role in immune cell infiltration, and could serve as potential novel targets for the prevention and diagnosis of DKD.