Faculty Collaboration Database

Genetic Deletion of β-Arrestin 2 From the Subfornical Organ and Other Periventricular Nuclei in the Brain Alters Fluid Homeostasis and Blood Pressure. Hypertension 2024 Jun;81(6):1332-1344

Date

04/17/2024

Pubmed ID

38629290

Pubmed Central ID

PMC11096025

DOI

10.1161/HYPERTENSIONAHA.124.22874

Abstract

BACKGROUND: ANG (angiotensin II) elicits dipsogenic and pressor responses via activation of the canonical Gαq (G-protein component of the AT₁R [angiotensin type 1 receptor])-mediated AT₁R in the subfornical organ. Recently, we demonstrated that ARRB2 (β-arrestin 2) global knockout mice exhibit a higher preference for salt and exacerbated pressor response to deoxycorticosterone acetate salt. However, whether ARRB2 within selective neuroanatomical nuclei alters physiological responses to ANG is unknown. Therefore, we hypothesized that ARRB2, specifically in the subfornical organ, counterbalances maladaptive dipsogenic and pressor responses to the canonical AT₁R signaling.

METHODS: Male and female Arrb2^FLOX mice received intracerebroventricular injection of either adeno-associated virus (AAV)-Cre-GFP (green fluorescent protein) to induce brain-specific deletion of ARRB2 (Arrb2^ICV-Cre). Arrb2^FLOX mice receiving ICV-AAV-GFP were used as control (Arrb2^ICV-Control). Infection with ICV-AAV-Cre primarily targeted the subfornical organ with few off targets. Fluid intake was evaluated using the 2-bottle choice paradigm with 1 bottle containing water and 1 containing 0.15 mol/L NaCl.

RESULTS: Arrb2^ICV-Cre mice exhibited a greater pressor response to acute ICV-ANG infusion. At baseline conditions, Arrb2^ICV-Cre mice exhibited a significant increase in saline intake compared with controls, resulting in a saline preference. Furthermore, when mice were subjected to water-deprived or sodium-depleted conditions, which would naturally increase endogenous ANG levels, Arrb2^ICV-Cre mice exhibited elevated saline intake.

CONCLUSIONS: Overall, these data indicate that ARRB2 in selective cardiovascular nuclei in the brain, including the subfornical organ, counterbalances canonical AT₁R responses to both exogenous and endogenous ANG. Stimulation of the AT₁R/ARRB axis in the brain may represent a novel strategy to treat hypertension.

Author List

Mathieu NM, Tan EE, Reho JJ, Brozoski DT, Muskus PC, Lu KT, Wackman KK, Grobe JL, Nakagawa P, Sigmund CD

Authors

Justin L. Grobe PhD Professor in the Physiology department at Medical College of Wisconsin
John J. Reho Research Scientist II in the Physiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Angiotensin II
Animals
Blood Pressure
Brain
Female
Homeostasis
Male
Mice
Mice, Knockout
Receptor, Angiotensin, Type 1
Subfornical Organ
beta-Arrestin 2