Aims Organs modulating blood pressure are associated with a common cytokine known as adipokines. We chose Zinc-alpha2-glycoprotein (ZAG) due to its prioritized transcriptional level in the database. Previous studies showed that ZAG is involved in metabolic disorders. The aim of this study was to investigate its role in hypertension. Methods and results Serum ZAG levels were assessed in hypertensive and healthy participants. Blood pressure was monitored in Azgp1−/− mice and other animal models by 24-hour ambulatory implanted telemetric transmitters and tail-cuff method. Multi-omics analysis of proteomics and metabolomics were performed to explore possible mechanisms. Serum ZAG levels were significantly decreased and associated with morning urine Na+ excretion in hypertensive participants in a cross-sectional study. This study firstly reported that Azgp1−/− mice exhibited increased blood pressure and impaired urinary Na+ excretion, which were restored by AAV9-mediated renal tubule Azgp1 rescue. Azgp1 knockout caused the reprogramming of renal lipid metabolism, and increased Na+/H+-exchanger (NHE) activity in the renal cortex. Administration with a NHE inhibitor EIPA reversed the impaired urinary Na+ excretion in Azgp1−/− mice. Moreover, the activity of carnitine palmitoyltransferase 1 (CPT1), a key enzyme of fatty acid β-oxidation, was decreased, and the levels of malonyl-CoA, an inhibitor of CPT1, were increased in renal cortex of Azgp1−/− mice. Renal Cpt1 rescue improved urinary Na+ excretion and blood pressure in Azgp1−/− mice, accompanied by decreased renal fatty acid levels and NHE activity. Finally, administration of recombinant ZAG protein improved blood pressure and urinary Na+ excretion in spontaneous hypertension rats. Conclusion Deficiency of Azgp1 increased the malonyl CoA-mediated inhibition of CPT1 activity, leading to renal lipid metabolism reprogramming, resulting in accumulated fatty acids and increased NHE activity, subsequently decreasing urinary Na+ excretion and causing hypertension. These findings may provide a potential kidney-targeted therapy in the prevention and treatment of hypertension.

中文翻译：

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锌-α2-糖蛋白通过调节高血压患者肾脂质代谢重编程介导的尿 Na+ 排泄来调节血压


目的 调节血压的器官与一种称为脂肪因子的常见细胞因子有关。我们选择 Zinc-alpha2-glycoprotein （ZAG） 是因为其在数据库中的优先转录水平。先前的研究表明 ZAG 与代谢紊乱有关。本研究的目的是探讨其在高血压中的作用。方法和结果 评估高血压和健康参与者的血清 ZAG 水平。通过 24 小时动态植入遥测发射器和尾套方法监测 Azgp1 −/− 小鼠和其他动物模型的血压。对蛋白质组学和代谢组学进行多组学分析，探讨可能的机制。在一项横断面研究中，高血压参与者的血清 ZAG 水平显着降低并与清晨尿液 Na + 排泄相关。本研究首先报道了 Azgp1-/-小鼠表现出血压升高和尿 Na+ 排泄受损，这些表现通过 AAV9 介导的肾小管 Azgp1 挽救而恢复。Azgp1 敲除导致肾脂质代谢重编程，并增加肾皮层中 Na+/H+-交换剂 （NHE） 活性。用 NHE 抑制剂 EIPA 给药可逆转 Azgp1 - / - 小鼠中受损的尿 Na + 排泄。此外，在 Azgp1 −/− 小鼠的肾皮层中，脂肪酸β氧化的关键酶肉碱棕榈酰转移酶 1 （CPT1） 的活性降低，丙二酰辅酶 A（CPT1 抑制剂）的水平升高。肾脏 Cpt1 拯救改善了 Azgp1 - / - 小鼠的尿 Na + 排泄和血压，并伴有肾脂肪酸水平和 NHE 活性降低。最后，重组 ZAG 蛋白的给药改善了自发性高血压大鼠的血压和尿 Na+ 排泄。 结论 Azgp1 缺乏增加了丙二酰辅酶 A 介导的 CPT1 活性抑制作用，导致肾脂质代谢重编程，导致脂肪酸积累和 NHE 活性增加，进而减少尿 Na+ 排泄并引起高血压。这些发现可能为高血压的预防和治疗提供潜在的肾脏靶向治疗。