Dataset Information

ARRB2 (β-Arrestin-2) Deficiency Alters Fluid Homeostasis and Blood Pressure Regulation.

ABSTRACT:

Background

GPCRs (G protein-coupled receptors) 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 noncanonical 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.

Methods

Global β-arrestin1 (Arrb1) and β-arrestin2 (Arrb2) knockout mice were employed to evaluate drinking behavior, and BP was evaluated in Arrb2-knockout 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 2-bottle choice paradigm with and without DOCA.

Results

Without DOCA (baseline), Arrb2-knockout mice exhibited a significant elevation in saline intake with no change in water intake. With DOCA treatment, Arrb2-knockout mice exhibited a significant increase in both saline and water intake. Although Arrb2-knockout 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-knockout and C57BL/6 mice with and without DOCA. Arrb2-knockout 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-knockout exhibited an increased pressor response to DOCA-salt.

Conclusions

These findings suggest that in salt-sensitive hypertension, ARRB2, but not ARRB1 (β-arrestin 1), might counterbalance the canonical signaling of GPCRs.

SUBMITTER: Mathieu NM

PROVIDER: S-EPMC9669141 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Publications

ARRB2 (β-Arrestin-2) Deficiency Alters Fluid Homeostasis and Blood Pressure Regulation.

Mathieu Natalia M NM Nakagawa Pablo P Grobe Connie C CC Reho John J JJ Brozoski Daniel T DT Lu Ko-Ting KT Wackman Kelsey K KK Ritter McKenzie L ML Segar Jeffrey L JL Grobe Justin L JL Sigmund Curt D CD

Hypertension (Dallas, Tex. : 1979) 20220823 11

<h4>Background</h4>GPCRs (G protein-coupled receptors) 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 noncanonical 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 prototyp ...[more]

PMID: 36215165

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Project description:RationaleAbdominal aortic aneurysms (AAAs) are a chronic inflammatory vascular disease for which pharmacological treatments are not available. A mouse model of AAA formation involves chronic infusion of angiotensin II (AngII), and previous studies indicated a primary role for the AngII type 1a receptor in AAA formation. β-arrestin (βarr)-2 is a multifunctional scaffolding protein that binds G-protein-coupled receptors such as AngII type 1a and regulates numerous signaling pathways and pathophysiological processes. However, a role for βarr2 in AngII-induced AAA formation is currently unknown.ObjectiveTo determine whether βarr2 played a role in AngII-induced AAA formation in mice.Methods and resultsTreatment of βarr2(+/+) and βarr2(-/-) mice on the hyperlipidemic apolipoprotein E-deficient (apoE(-/-)) background or on normolipidemic C57BL/6 background with AngII for 28 days indicated that βarr2 deficiency significantly attenuated AAA formation. βarr2 deficiency attenuated AngII-induced expression of cyclooxygenase-2, monocyte chemoattractant protein-1, macrophage inflammatory protein 1α, and macrophage infiltration. AngII also increased the levels of phosphorylated extracellular signal-regulated kinase 1/2 in apoE(-/-)/βarr2(+/+) aortas, whereas βarr2 deficiency diminished this increase. Furthermore, inhibition of extracellular signal-regulated kinase 1/2 activation with CI1040 (100 mg/kg per day) reduced the level of AngII-induced cyclooxygenase-2 expression in apoE(-/-)/βarr2(+/+) mice to the level observed in apoE(-/-)/βarr2(-/-) mice. AngII treatment also increased matrix metalloproteinase expression and disruption of the elastic layer in apoE(-/-)/βarr2(+/+) aortas, and βarr2 deficiency reduced these effects.Conclusionsβarr2 contributes to AngII-induced AAA formation in mice by phosphorylated extracellular signal-regulated kinase 1/2-mediated cyclooxygenase-2 induction and increased inflammation. These studies suggest that for the AngII type 1a receptor, G-protein-independent, βarr2-dependent signaling plays a major role in AngII-induced AAA formation.

Dataset Information

ARRB2 (β-Arrestin-2) Deficiency Alters Fluid Homeostasis and Blood Pressure Regulation.

Background

Methods

Results

Conclusions

Publications

ARRB2 (β-Arrestin-2) Deficiency Alters Fluid Homeostasis and Blood Pressure Regulation.

Similar Datasets

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