ARRB2 (β-Arrestin-2) Deficiency Alters Fluid Homeostasis and Blood Pressure Regulation.
ARRB2 (β-Arrestin-2) Deficiency Alters Fluid Homeostasis and Blood Pressure Regulation.
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DOI：
10.1161/hypertensionaha.122.19863
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发表时间：
2022-11
期刊：
影响因子：
8.3
通讯作者：
Sigmund, Curt D.
中科院分区：
文献类型：
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作者：
Mathieu, Natalia M.;Nakagawa, Pablo;Grobe, Connie C.;Reho, John J.;Brozoski, Daniel T.;Lu, Ko-Ting;Wackman, Kelsey K.;Ritter, McKenzie L.;Segar, Jeffrey L.;Grobe, Justin L.;Sigmund, Curt D.
G蛋白偶联受体（GPCR）与血压（BP）和液体摄入调节有关。有一个发展中的概念，这些作用是由经典G蛋白信号传导和非经典β-抑制蛋白介导的信号传导介导的，但每一个的贡献仍然在很大程度上未被探索。在此，我们假设β-arrestin有助于醋酸脱氧皮质酮（DOCA）-盐性高血压（盐敏感性高血压的原型模型）的液体稳态和血压（BP）调节。采用β-arrestin 1（Arrb 1）和β-arrestin 2（Arrb 2）基因敲除（KO）小鼠评估饮酒行为，并评估Arrb 2-KO小鼠的血压。年龄和性别匹配的C57 BL/6小鼠作为对照。我们测量了摄入的水和不同的氯化钠溶液和BP采用两瓶选择范例与DOCA和不。在没有DOCA（基线）的情况下，Arrb 2-KO小鼠表现出盐水摄入量的显著升高，而水摄入量没有变化。用DOCA处理，Arrb 2-KO小鼠表现出盐水和水摄入量的显著增加。虽然Arrb 2-KO小鼠在基线条件下表现出高钠血症，但我们没有发现全身钠储存或钠适口性的显著变化。在另一个队列中，通过遥测术测量了Arrb 2-KO和C57 BL/6小鼠（有和无DOCA）的BP。在DOCA治疗前，当单独提供水时，或当提供水和盐水的选择时，Arrb 2-KO没有表现出显著的BP差异。然而，Arrb 2-KO表现出对DOCA-盐的升压反应增加。这些发现表明，在盐敏感性高血压中，ARRB 2，而不是ARRB 1，可能会抵消GPCR的经典信号。
G protein-coupled receptors (GPCRs) are implicated in blood pressure (BP) and fluid intake regulation. There is a developing concept that these effects are mediated by both canonical G-protein signaling and non-canonical β-arrestin mediated signaling, but the contributions of each remain largely unexplored. Here, we hypothesized that β-arrestin contributes to fluid homeostasis and blood pressure (BP) regulation in deoxycorticosterone acetate (DOCA)-salt hypertension, a prototypical model of salt-sensitive hypertension. Global β-arrestin1 (Arrb1) and β-arrestin2 (Arrb2) knockout (KO) mice were employed to evaluate drinking behavior, and BP was evaluated in Arrb2-KO mice. Age- and sex-matched C57BL/6 mice served as controls. We measured intake of water and different sodium chloride solutions and BP employing a two-bottle choice paradigm with and without DOCA. Without DOCA (baseline), Arrb2-KO mice exhibited a significant elevation in saline intake with no change in water intake. With DOCA treatment, Arrb2-KO mice exhibited a significant increase in both saline and water intake. Although, Arrb2-KO mice exhibited hypernatremia at baseline conditions, we did not find significant changes in total body sodium stores or sodium palatability. In a separate cohort, BP was measured via telemetry in Arrb2-KO and C57BL/6 mice with and without DOCA. Arrb2-KO did not exhibit significant differences in BP before DOCA treatment when provided water alone, or when provided a choice of water and saline. However, Arrb2-KO exhibited an increased pressor response to DOCA-salt. These findings suggest that in salt-sensitive hypertension, ARRB2, but not ARRB1, might counterbalance the canonical signaling of GPCRs.