Role of β‐Arrestin2 as a Regulator of Fluid Homeostasis and Blood Pressure

Abstract

Low‐renin hypertension is a common subset of hypertensive patients, which is associated with salt sensitivity. Deoxycorticosterone (DOCA)‐salt hypertension, a prototypical model of low‐renin hypertension, requires activation of the angiotensin type‐1 receptor (AT1R) in specific brain areas. The canonical G‐protein‐mediated signaling of the AT1R is known to induce pressor responses while the non‐canonical β‐Arrestin mediated signaling is thought to counterbalance the detrimental effects of canonical signaling. We hypothesized that β‐Arrestin activation contributes to fluid homeostasis and blood pressure (BP) regulation in DOCA‐salt hypertension. Global β‐Arrestin1 (Arrb1) and β‐Arrestin2 (Arrb2) knockout (KO) mice were employed to evaluate drinking behavior and BP. Age‐ and sex‐matched C57BL/6J mice served as controls. Mice were subjected to the two‐bottle choice paradigm, in which the animals were presented with two bottles, one containing water and one containing varying concentrations of NaCl (0.15, 0.30, and 0.45 mol/L). At baseline, Arrb2‐KO mice exhibited a significant increase in saline intake when presented with 0.15M and 0.30M but not 0.45M (WT0.15M=2.4±0.8 and WT0.30M 1.2±0.4 vs Arrb2‐KO0.15M=4±1.7 and Arrb2‐KO0.30M=2.3±1.1 mL/day; p0.15M=0.23 and p0.30M<0.05; n=19 and 24, respectively). This resulted in a saline preference, which means mice preferred saline over water by more than 50% by volume. Under DOCA, Arrb2‐KO, but not Arrb1‐KO, exhibited a significant increase in saline intake when presented with 0.15M and 0.30M, but not 0.45M saline (WT0.15M=10.9±3.6 and WT0.30M 3.8±2 vs Arrb2‐KO0.15M=15.2±6.3 and Arrb2‐KO0.30M=6±2 mL/day; p<0.05; n=19 and 24, respectively) when compared with wildtype. In addition, Arrb2‐KO mice showed a significant increase in fluid intake when presented to 0.15M, 0.30M, and 0.45M saline. Telemetric BP was measured under three conditions: 1) baseline without saline in drinking water 2) baseline with a choice of saline and water, and 3) administration with DOCA with a choice of saline and water. Arrb2‐KO did not exhibit significant differences in BP in absence of DOCA infusion when given water alone or a choice for saline. However, Arrb2‐KO exhibited an increase in the pressor response to DOCA‐salt (WT=152.2±11.9 vs Arrb2‐KO=163.7±4.2 mmHg; p=0.18; n=6). Surprisingly, no alterations in water intake, saline intake, total fluid intake, saline preference, or BP was observed in Arrb1 KO at any given saline concentration under either baseline or DOCA condition. These findings suggest that in low renin hypertension, Arrb2, but not Arrb1, might counterbalance the detrimental canonical signaling of pathological G protein‐coupled receptors including AT1R.