Human plasma metabolomics reveals metabolic targets for intervention in salt-sensitive hypertension

Salt-sensitive hypertension (SSH) is a major risk factor for cardiovascular disease, but its metabolic mechanisms remain unclear. This study investigates the plasma metabolic profile of SSH patients to identify potential therapeutic targets. Additionally, SSH patients were identified through an oral salt-loading test. Plasma metabolomics was performed by utilizing GC-MS and LC-MS, followed by network correlation analysis, pathway enrichment, receiver operating characteristic analysis, and linear regression analysis. The findings were validated in Dahl salt-sensitive (SS) rats, with glycine supplementation evaluated as a potential therapeutic intervention. Firstly, plasma metabolomics illustrated distinct metabolic alterations in SSH patients, with substantially increased levels of fumaric acid, pyruvat,e and lactic acid, as well as significantly decreased levels of glycine, leucine and β-alanine (p < 0.05). Additionally, Glycine and β-alanine levels decreased by 61% and 68% compared to the control group. Secondly, pathway enrichment analysis identified disruptions in amino acid metabolism, particularly Arginine biosynthesis pathway, TCA pathway, glycine, serine, and threonine metabolism pathways were significantly enriched (p < 0.05). Correlation network analysis identified fumarate as a hub metabolite in the pathophysiology of SSH. Glycine showed the highest predictive value for SSH (AUC = 94.6181%) and was negatively correlated with blood pressure. Finally, glycine supplementation in SS rats substantially reduced salt-induced hypertension (p < 0.001) by improving renal amino acid metabolism and enhancing nitric oxide production. This study identifies glycine as a crucial metabolic target for SSH intervention. Glycine supplementation effectively alleviates SSH in animal models, indicating its potential for clinical applications. Future research should focus on exploring glycine-based therapies in clinical trials. (Figure presented.)