Key result
Arrb2-knockout mice exhibited significantly increased saline and water intake and an increased pressor response to DOCA-salt compared to controls in a model of salt-sensitive hypertension.
Why the study?
The distinct contributions of canonical G protein versus noncanonical beta-arrestin signaling to blood pressure and fluid intake regulation remain largely unexplored.
Does ARRB2 deficiency alter fluid homeostasis and blood pressure regulation in a DOCA-salt hypertension mouse model?
Does ARRB2 deficiency alter fluid homeostasis and blood pressure regulation in a DOCA-salt hypertension mouse model?
ARRB2 deficiency increases saline intake and exacerbates the pressor response to DOCA-salt, suggesting it counterbalances canonical GPCR signaling in salt-sensitive hypertension.
β-arrestin contributions to BP regulation in DOCA-salt hypertension remain hypothesis-generating; human studies required before clinical relevance.
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.
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Mathieu et al. (2022) studied Salt-sensitive hypertension. Arrb2 (β-Arrestin-2) knockout vs. Age- and sex-matched C57BL/6 mice was evaluated on Fluid intake (water and saline) and blood pressure. Arrb2-knockout mice exhibited significantly increased saline and water intake and an increased pressor response to DOCA-salt compared to controls in a model of salt-sensitive hypertension.
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