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 SHRs. Conclusions 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-糖蛋白通过调节肾脏脂质代谢重编程调节血压 - 介导高血压尿 Na+ 排泄


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。我们选择锌-α2-糖蛋白（ZAG）是因为它在数据库中优先转录水平。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 对高血压和健康参与者的血清 ZAG 水平进行了评估。通过24小时动态植入遥测发射器和尾套法监测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以探索可能的机制。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，并与晨尿 Na+ 排泄相关。本研究首次报道Azgp1-/-小鼠表现出血压升高和尿Na+排泄受损，但通过AAV9介导的肾小管Azgp1拯救得以恢复。 Azgp1 敲除导致肾脂质代谢重新编程，并增加肾皮质中 Na+/H+-交换器 (NHE) 活性。给予 NHE 抑制剂 EIPA 可以逆转 Azgp1-/- 小鼠尿 Na+ 排泄受损的情况。此外，Azgp1-/-小鼠肾皮质中脂肪酸β-氧化的关键酶肉碱棕榈酰转移酶1（CPT1）的活性降低，CPT1抑制剂丙二酰辅酶A的水平升高。肾 Cpt1 救援改善了 Azgp1-/- 小鼠的尿 Na+ 排泄和血压，同时降低了肾脂肪酸水平和 NHE 活性。最后，重组 ZAG 蛋白的施用改善了 SHR 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，导致肾脏脂质代谢重编程，导致脂肪酸积累和NHE活性增加，随后尿Na+排泄减少并导致高血压。这些发现可能为预防和治疗高血压提供潜在的肾脏靶向治疗。