FGF21 attenuates salt-sensitive hypertension via regulating HNF4α/ACE2 axis in the hypothalamic paraventricular nucleus of mice.

IF 1.5 4区 医学 Q3 PERIPHERAL VASCULAR DISEASE Clinical and Experimental Hypertension Pub Date : 2024-12-31 Epub Date: 2024-06-06 DOI:10.1080/10641963.2024.2361671
Wei Xu, Xia Gao, Hao Luo, Yingmei Chen
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Abstract

Background: Fibroblast growth factor 21 (FGF21) has a protective effect against cardiovascular disease. However, the role of FGF21 in hypertension remains elusive.

Methods: Ten-week-old male C57BL/6 mice were randomly divided into normal-salt (NS) group, NS+FGF21 group, deoxycorticosterone acetate-salt (DOCA) group and DOCA+FGF21 group. The mice in NS group underwent uninephrectomy without receiving DOCA and 1% NaCl and the mice in DOCA group were subjected to uninephrectomy and DOCA-salt (DOCA and 1% NaCl) treatment for 6 weeks. At the same time, the mice were infused with vehicle (artificial cerebrospinal fluid, aCSF) or FGF21 (1 mg/kg) into the bilateral paraventricular nucleus (PVN) of mice.

Results: Here, we showed that FGF21 treatment lowered DOCA salt-induced inflammation and oxidative stress in the PVN, which reduced sympathetic nerve activity and hypertension. Mechanistically, FGF21 treatment decreased the expression of HNF4α and inhibited the binding activity of HNF4α to the promoter region of ACE2 in the PVN of DOCA salt-treated mice, which further up-regulated ACE2/Ang (1-7) signals in the PVN. In addition, ACE2 deficiency abolished the protective effect of FGF21 in DOCA salt-treated mice, suggesting that FGF21-mediated antihypertensive effect was dependent on ACE2.

Conclusions: The results demonstrate that FGF21 protects against salt-sensitive hypertension via regulating HNF4α/ACE2/Ang (1-7) axis in the PVN of DOCA salt-treated mice via multi-organ crosstalk between liver, brain and blood vessels.

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FGF21通过调节小鼠下丘脑室旁核的HNF4α/ACE2轴减轻盐敏感性高血压。
背景:成纤维细胞生长因子 21(FGF21成纤维细胞生长因子 21(FGF21)对心血管疾病具有保护作用。然而,FGF21在高血压中的作用仍不明确:方法:10周龄雄性C57BL/6小鼠随机分为正常盐(NS)组、NS+FGF21组、醋酸去氧皮质酮盐(DOCA)组和DOCA+FGF21组。NS组小鼠在不接受DOCA和1% NaCl治疗的情况下接受肾切除术,DOCA组小鼠在不接受肾切除术的情况下接受DOCA-盐(DOCA和1% NaCl)治疗6周。同时,向小鼠双侧室旁核(PVN)注入载体(人工脑脊液,aCSF)或 FGF21(1 mg/kg):结果:我们在这里发现,FGF21 治疗可降低 DOCA 盐诱导的 PVN 炎症和氧化应激,从而降低交感神经活性和高血压。从机制上讲,FGF21治疗降低了HNF4α的表达,抑制了HNF4α与DOCA盐治疗小鼠PVN中ACE2启动子区域的结合活性,从而进一步上调了PVN中ACE2/Ang(1-7)信号。此外,ACE2的缺失可消除FGF21对DOCA盐处理小鼠的保护作用,这表明FGF21介导的降压作用依赖于ACE2:结论:研究结果表明,FGF21通过调节DOCA盐处理小鼠PVN中的HNF4α/ACE2/Ang(1-7)轴,并通过肝脏、大脑和血管之间的多器官串联,对盐敏感性高血压起到保护作用。
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来源期刊
CiteScore
3.90
自引率
0.80%
发文量
66
审稿时长
6-12 weeks
期刊介绍: Clinical and Experimental Hypertension is a reputable journal that has converted to a full Open Access format starting from Volume 45 in 2023. While previous volumes are still accessible through a Pay to Read model, the journal now provides free and open access to its content. It serves as an international platform for the exchange of up-to-date scientific and clinical information concerning both human and animal hypertension. The journal publishes a wide range of articles, including full research papers, solicited and unsolicited reviews, and commentaries. Through these publications, the journal aims to enhance current understanding and support the timely detection, management, control, and prevention of hypertension-related conditions. One notable aspect of Clinical and Experimental Hypertension is its coverage of special issues that focus on the proceedings of symposia dedicated to hypertension research. This feature allows researchers and clinicians to delve deeper into the latest advancements in this field. The journal is abstracted and indexed in several renowned databases, including Pharmacoeconomics and Outcomes News (Online), Reactions Weekly (Online), CABI, EBSCOhost, Elsevier BV, International Atomic Energy Agency, and the National Library of Medicine, among others. These affiliations ensure that the journal's content receives broad visibility and facilitates its discoverability by professionals and researchers in related disciplines.
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