Dissanayake Lashodya V, Smith Brody A, Zietara Adrian, Levchenko Vladislav, Lowe Melissa, Kravtsova Olha, Shapiro Abigail, Upadhyay Gunjan, Halade Ganesh V, Geurts Aron M, Palygin Oleg, Staruschenko Alexander
Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States.
Department of Internal Medicine, Heart Institute, University of South Florida, Tampa, Florida, United States.
Am J Physiol Cell Physiol. 2025 Oct 1;329(4):C1188-C1202. doi: 10.1152/ajpcell.00485.2025. Epub 2025 Sep 2.
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 () rats were used for further studies. At baseline, rats exhibited lower urinary excretion of tricarboxylic acid cycle metabolites compared with wild-type littermates, suggesting altered mitochondrial metabolism. Under an HS diet, 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. 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.
肉碱棕榈酰转移酶2（CPT2）是线粒体脂肪酸氧化（FAO）中的关键酶，这一过程对肾脏能量稳态至关重要。FAO的破坏以及血浆酰基肉碱（与肉碱结合的脂肪酸）的积累与肾脏和血管疾病有关。尽管肾脏严重依赖FAO，但CPT2缺乏的具体肾脏后果仍知之甚少。临床数据表明，CPT2表达可能与接受抗高血压治疗患者的寿命延长有关，但CPT2与高血压之间的直接联系尚未确立。我们之前在盐敏感（SS）高血压方面的研究表明，高盐（HS）饮食会增加FAO，同时降低肾脏酰基肉碱水平。为了研究CPT2缺乏在饮食应激下如何影响肾功能和代谢调节，我们在Dahl SS背景下创建了一种新型的CPT2缺陷大鼠模型。纯合敲除在胚胎期致死；因此，杂合（）大鼠用于进一步研究。在基线时，与野生型同窝仔鼠相比，大鼠三羧酸循环代谢物的尿排泄较低，表明线粒体代谢发生改变。在HS饮食下，大鼠血压无显著差异。然而，当面对高盐生酮饮食时，这些大鼠表现出一些矛盾的影响，血压较低，同时伴有脂质失调和长链酰基肉碱积累。总的来说，我们的研究结果揭示了CPT2在对SS高血压的代谢和病理生理反应中的复杂作用，对饮食应激下的肾脏和心血管结局具有影响。尽管高盐饮食已被证明对心血管健康有负面影响，但生酮饮食已显示出有益效果。在当前研究中，我们在盐敏感背景下创建了CPT2缺乏模型，并表明两种饮食的组合对脂肪酸失调模型有意外影响，似乎减少了高血压的发生。我们的数据表明CPT2在调节血压方面具有复杂作用，其作用超出了脂肪酸氧化。
