Integrative multi‐omics suggests core gene dysregulation of histidine metabolism in diabetic kidney disease

AIMS: To investigate the role of histidine metabolism in diabetic kidney disease (DKD), we analysed histidine metabolism-related genes using an integrative multi-omics approach. METHODS: Untargeted metabolomics was performed on serum from DKD persons and healthy controls, as well as on high glucose-treated and normal glucose-treated HK-2 cells, to assess metabolic alterations. We also analysed publicly available datasets, including GEO transcriptomes, Kidney Precision Medicine Project (KPMP), Kidney Interactive Transcriptomics single-cell data, the Human Protein Atlas (HPA) and Nephroseq, to examine the expression and function of histidine metabolism-related genes. RESULTS: Serum metabolomics confirmed alterations in histidine metabolism. Single-cell analysis revealed that five histidine metabolism-related genes were expressed in proximal tubular epithelial cells and significantly downregulated in DKD. Immunohistochemistry data from the HPA further demonstrated that the corresponding proteins are localized in the proximal tubule (PT). High-glucose treatment suppressed histidine metabolism in HK-2 cells, supporting specific metabolic reprogramming. Clinical correlation analyses using Nephroseq linked the decreased expression of these genes to renal function decline. Collectively, these findings indicate that histidine metabolic disruption is associated with tubular cell dysfunction, suggesting a mechanistic contribution to DKD progression. CONCLUSION: By integrating multi-omics analyses, we suggest that histidine metabolic reprogramming represents a PT pathological event in DKD, providing novel mechanistic insights and potential therapeutic targets.