NADPH Oxidase 4 and Metabolic Stress in Dahl Salt-Sensitive Rat Kidneys. Hypertension 2026 Mar;83(3):e25718
Date
12/10/2025Pubmed ID
41368709DOI
10.1161/HYPERTENSIONAHA.125.25718Scopus ID
2-s2.0-105035611538 (requires institutional sign-in at Scopus site) 5 CitationsAbstract
BACKGROUND: Salt-sensitive (SS) hypertension is associated with oxidative stress and impaired renal metabolism, but the mechanistic link remains unclear. We investigated the role of NOX4 (NADPH oxidase 4)-derived reactive oxygen species in shaping renal metabolic and vascular responses to high-salt intake in SS hypertension.
METHODS: Male Dahl SS and SSNOX4-/- rats were maintained on a low-salt (0.4% NaCl) diet and then exposed to high salt (4.0% NaCl) for 21 days. Mean arterial pressure and renal blood flow were continuously measured, with intermittent arterial and renal venous sampling. The glomerular filtration rate was measured in separate groups of rats. Transcriptomic and metabolomic profiling of renal cortex, outer medulla, plasma, and urine was performed.
RESULTS: High-salt intake led to progressive hypertension in SS rats, accompanied by transcriptomic and metabolic patterns suggestive of increased glutamate utilization, redox imbalance, and elevated reactive oxygen species. This glutamine-related profile was associated with high oxygen demand, increased proteolysis, and reduced adaptability in substrate utilization. SSNOX4-/- rats exhibited attenuated hypertension, preserved redox balance, and increased nitric oxide bioavailability. Their kidneys exhibited metabolic patterns suggestive of greater reliance on fatty acid oxidation, with indications of improved oxygen efficiency, reduced amino acid catabolism, and lactate release without upregulating glycolytic genes. The glomerular filtration rate and renal blood flow changes were similar between strains.
CONCLUSIONS: NOX4-derived reactive oxygen species were linked to less favorable metabolic responses to salt loading in SS hypertension. NOX4 deletion was associated with a more protective, fatty acid oxidation-driven metabolic profile. These findings highlight redox-sensitive metabolic reprogramming as a potential therapeutic target in hypertension and chronic kidney disease.
Author List
Shimada S, Yang C, Hoffmann BR, Stodola TJ, Kurth T, Liang M, Dash RK, Cowley AW JrAuthors
Allen W. Cowley PhD Professor in the Physiology department at Medical College of WisconsinRanjan K. Dash PhD Professor in the Biomedical Engineering department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsBlood Pressure
Disease Models, Animal
Glomerular Filtration Rate
Hypertension
Kidney
Male
NADPH Oxidase 4
Oxidative Stress
Rats
Rats, Inbred Dahl
Reactive Oxygen Species
Sodium Chloride, Dietary
