Untargeted metabolomic and proteomic analysis implicates SIRT2 as a novel therapeutic target for diabetic nephropathy.

Diabetic nephropathy (DN) is one of the major causes of end-stage renal disease. This study aimed to explore the internal relationship between metabolic processes and autoimmune responses in patients with DN via untargeted metabolomics and Olink proteomics. The serum of 10 patients who were diagnosed with DN and 10 healthy individuals via untargeted metabolomics and Olink proteomics. Animal models were used to validate the characterized genes. Correlation analysis of major differentially abundant metabolites and differentially expressed proteins revealed that SIRT2 might be a key hub linking energy metabolism and innate immune responses. KEGG enrichment analysis showed that HIF-1 signaling pathway and renal cell carcinoma pathway were co-enriched pathways in energy metabolism and inflammatory response. VEGFA plays a vital role in these two signaling pathways. The ability of SIRT2 to regulate VEGFA expression has been demonstrated. In vivo experiments revealed that SIRT2, VEGFA, and HIF-1α were highly expressed in the kidneys of mice with diabetic nephropathy. In conclusion, our study combines metabolomics and proteomics to provide valuable insights into the synergistic roles of metabolic disorders and inflammatory responses in DN. The data suggest that SIRT2 may be a key target affecting these processes.