Role of NAD metabolism-related genes in diabetic nephropathy: subtype classification, biomarker identification, and...

Diabetic nephropathy (DN) remains a major complication of diabetes, significantly impacting renal function. Emerging evidence suggests that NAD metabolism plays a crucial role in DN pathogenesis. This study investigates the roles of NAD metabolism-related genes in DN and how there are associated with different disease subtypes. We analyzed gene expression data from DN-associated datasets (GSE30528 and GSE30529) to identify differences in NAD metabolism-related genes between normal and DN samples. We classified DN into subtypes based on NAD gene expression and evaluated NAD scores using ssGSEA. Immune cell infiltration and pathway analyses were assessed using ssGSEA, Microenvironment Cell Populations-counter (MCPcounter), and Gene Set Variation Analysis (GSVA). Key biomarker genes were identified using machine learning algorithms and validated across multiple datasets. We further explored the relationship between gene expression and kidney function using the Nephroseq V5 tool. Thirteen differentially expressed NAD metabolism-related genes were identified, with distinctive expression patterns observed between normal and DN samples. Two distinct NAD-related subtypes were classified, demonstrating significant differences in gene expression, immune cell infiltration, and pathway activities. Immune-related pathways and cellular processes exhibited varied enrichment between subtypes. Six key NAD metabolism-related genes (FMO3, ALDH1A3, FMO5, TKT, LBR, HPGD) were identified as potential biomarkers. Higher levels of FMO3, ALDH1A3, TKT, and LBR were linked to worse kidney function, while FMO5 and HPGD were associated with better kidney function. The study highlights the significant involvement of NAD metabolism-related genes in DN pathogenesis and their association with disease subtypes and renal function. The identified biomarkers could be targets for new treatments and provide insight for future DN research.