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The present study investigates the therapeutic potential and underlying mechanisms of fenofibrate, a peroxisome proliferator-activated receptor \u03b1 (PPAR\u03b1) activator, in SSH. Clinical observations indicate that SSH in male patients is often accompanied by dyslipidemia, with a positive correlation observed between blood pressure and lipid profiles\u2014particularly triglycerides. In male Dahl salt-sensitive (SS) rats, a four-week oral administration of fenofibrate (100 mg\/kg\/day) prevented high-salt diet (HSD)-induced hypertension, dyslipidemia, and renal injury, without affecting body weight or food intake. Renal untargeted metabolomics demonstrated that HSD induced significant alterations in amino acid metabolism, the TCA cycle, pentose phosphate pathway, and arginine biosynthesis. Fenofibrate treatment reversed these metabolic abnormalities, notably restoring the levels of key amino acids such as arginine, serine, and branched-chain amino acids. Furthermore, fenofibrate stimulated the expression of renal PPAR\u03b1 and PPAR\u03b3. It potentiated nitric oxide (NO) synthesis by up-regulating endothelial nitric oxide synthase protein expression and increasing arginine availability, improved the redox balance by enhancing antioxidant capacity, and elevated the cellular energy charge in the kidney. These findings demonstrate that fenofibrate ameliorates SSH by restoring renal metabolic homeostasis, enhancing NO synthesis, reducing oxidative stress, and improving bioenergetics, highlighting its promise as a therapeutic strategy for SSH, particularly in male patients with concurrent hyperlipidemia.<\/jats:p>","DOI":"10.1042\/cs20250379","type":"journal-article","created":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T11:19:42Z","timestamp":1771499982000},"page":"469-489","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Fenofibrate ameliorates salt-sensitive hypertension by improving renal metabolic homeostasis"],"prefix":"10.1042","volume":"140","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5260-3880","authenticated-orcid":false,"given":"Pengfei","family":"Yang","sequence":"first","affiliation":[{"name":"1Department of Cardiovascular Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China"},{"name":"2The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingxiao","family":"Liu","sequence":"additional","affiliation":[{"name":"2The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuchen","family":"Li","sequence":"additional","affiliation":[{"name":"2The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luxin","family":"Zhou","sequence":"additional","affiliation":[{"name":"2The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Limei","family":"Wu","sequence":"additional","affiliation":[{"name":"2The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Di","family":"Gao","sequence":"additional","affiliation":[{"name":"2The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhe","family":"Yang","sequence":"additional","affiliation":[{"name":"2The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Zeng","sequence":"additional","affiliation":[{"name":"3College of Medical Technology and Engineering, Henan University of Science and Technology, Luoyang, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuewei","family":"Zheng","sequence":"additional","affiliation":[{"name":"3College of Medical Technology and Engineering, Henan University of Science and Technology, Luoyang, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianjun","family":"Mu","sequence":"additional","affiliation":[{"name":"1Department of Cardiovascular Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhongmin","family":"Tian","sequence":"additional","affiliation":[{"name":"1Department of Cardiovascular Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China"},{"name":"2The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2026,3,11]]},"reference":[{"key":"2026031103161917300_B1","doi-asserted-by":"publisher","first-page":"2350","DOI":"10.1016\/j.jacc.2023.11.007","article-title":"Global burden of cardiovascular diseases and risks, 1990-2022","volume":"82","author":"Mensah","year":"2023","journal-title":"J. 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