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

Hypertension Research volume 48, pages 2567–2583 (2025)Cite this article

Abstract

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.

Intervention targets and validation of salt-sensitive hypertension

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Acknowledgements

We are very grateful to Qingjian County People’s Hospital in Yulin, Shaanxi Province for their support and assistance during the plasma sample collection process. We were very grateful to the animal wardens (Ying Guo) for taking care of the rats before this experiment. We are grateful to Xiao-Fei Wang and Lin Han (Biomedical Experimental Center of Xi’an Jiaotong University) for their technical support. We thank Shanghai Tengyun Biotechnology Co., Ltd. for developing Hiplot Pro platform and providing technical assistance.

Funding

This work was supported by the National Natural Science Foundation of China (Grant numbers 82370726 and 82400684), Shaanxi Province Postdoctoral Science Foundation [grant number 2024BSHYDZZ003], Youth Project of the Basic Research Program of Shaanxi Provincial Natural Science Foundation (Grant number 2025JC-YBQN-1193) and the Fundamental Research Funds for the Central Universities (Grant number sxzy012025067).

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  1. These authors contributed equally: Pengfei Yang, Xiangbo Chen.

Authors and Affiliations

  1. Department of Cardiovascular Medicine, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China

    Pengfei Yang, Yang Wang & Jianjun Mu

  2. The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, China

    Pengfei Yang, Xiangbo Chen, Mingxiao Liu, Xian Li, Tailin Wu, Zhe Yang, Di Gao & Zhongmin Tian

  3. Xi’an People’s Hospital (Xi’an Fourth Hospital), School of Life Sciences and Medicine, Northwest University, Xi’an, China

    Yanan Ouyang

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  1. Pengfei Yang
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Yang, P., Chen, X., Liu, M. et al. Human plasma metabolomics reveals metabolic targets for intervention in salt-sensitive hypertension. Hypertens Res 48, 2567–2583 (2025). https://doi.org/10.1038/s41440-025-02280-2

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