NADPH Oxidase 4 and Metabolic Stress in Dahl Salt-Sensitive Rat Kidneys

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.

Male Dahl SS and SS^NOX4-/- 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.

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. SS^NOX4-/- 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.

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.