The role of carnitine palmitoyl transferase 2 in the progression of salt-sensitive hypertension.

Carnitine palmitoyl transferase 2 (CPT2) is a key enzyme in mitochondrial fatty acid oxidation (FAO), a process critical for renal energy homeostasis. Disruption of FAO and accumulation of plasma acylcarnitines (fatty acids conjugated to carnitine) have been implicated in renal and vascular diseases. Although the kidney relies heavily on FAO, the specific renal consequences of CPT2 deficiency remain poorly understood. Clinical data suggest that CPT2 expression may be associated with increased lifespan in patients on antihypertensive therapy, yet a direct link between CPT2 and hypertension has not been established. Our previous work in salt-sensitive (SS) hypertension showed that a high-salt (HS) diet increases FAO while reducing renal acylcarnitine levels. To investigate how CPT2 deficiency affects renal function and metabolic regulation under dietary stress, we generated a novel CPT2-deficient rat model on the Dahl SS background. Homozygous knockouts were embryonically lethal; thus, heterozygous (SS^Cpt2+/-) rats were used for further studies. At baseline, SS^Cpt2+/- rats exhibited lower urinary excretion of tricarboxylic acid cycle metabolites compared with wild-type littermates, suggesting altered mitochondrial metabolism. Under an HS diet, SS^Cpt2+/- rats had no significant differences in blood pressure. However, when faced with a high-salt ketogenic diet, these rats exhibited somewhat contradictory effects, showing lower blood pressure alongside lipid dysregulation and accumulation of long-chain acylcarnitines. Collectively, our findings reveal a complex role for CPT2 in the metabolic and pathophysiological responses to SS hypertension, with implications for renal and cardiovascular outcomes under dietary stress.NEW & NOTEWORTHY Although high-salt diets have been shown to negatively impact cardiovascular health, the ketogenic diet has demonstrated beneficial effects. In the current study, we created a model of CPT2 deficiency on a salt-sensitive background and showed that the combination of both diets has an unexpected effect on a model of fatty acid dysregulation, seemingly reducing the development of hypertension. Our data suggest a complex role for CPT2, extending beyond fatty acid oxidation, in regulating blood pressure.