Abstract Body: Introduction: T-cells contribute to hypertension (HT) development. Among several G-protein coupled receptors regulating T-cell function, it has been hypothesized that some subpopulations use the angiotensin II (ANG II) type 1 receptor (AT₁R) to modulate immune responses in HT. Selective ablation of AT₁Rs in T-cells paradoxically increases hypertensive end-organ damage (EOD). While AT₁Rs typically induces classical G-protein signaling, recent studies have uncovered a protective signaling cascade via β-arrestin (ARRB) proteins. We hypothesize that T-cell ARRBs mediate an anti-hypertensive and anti-inflammatory role in response to ANG II, decreasing EOD in HT.
Methods: Breeding CD4-Cre mice with Arrb1-Flox or Arrb2-Flox mice generated lines with T-cell-specific deficiency of Arrb1 or Arrb2 genes. Hypertensive conditions modeling kidney damage consisted of unilateral nephrectomy, 4% salt diet, and continuous infusion of 1 mg/kg/min ANG II (UNX/HSD/ANG). Age/sex-matched Cre^- littermates were used as controls (WT). Blood pressure (BP) was measured at baseline and for the following three weeks using radiotelemetry.
Results: At baseline, there were no significant differences in systolic BP between groups (WT:124.1±8.0 mmHg; CD4^Arrb1-null:125.4±8.1; CD4^Arrb2-null:128.7±3.1; p=0.37; n=12/10/8). Three weeks of UNX/HSD/ANG equally increased systolic BP in all groups (WT:178.0±14.0 mmHg; CD4^Arrb1-null:174.8±26.3; CD4^Arrb2-null:179.9±11.1; p=0.86; n=7/9/7). Despite similar BPs, CD4^Arrb2-null mice demonstrated less renal inflammation than WT after four weeks of UNX/HSD/ANG, with a reduction in interleukin-1α protein (3.8±3.2 vs. 8.3±2.8 p<0.05; n=4/6) and a trend towards decreased tumor necrosis factor-α transcript (0.63-fold change vs. 1.9, p=0.051; n=10/8). Furthermore, CD4^Arrb1-null mice increased 24-hour voluntary water intake compared to WT (15.7±3.4 mL vs. 12.2±1.6; p<0.05; n=12/7), and 24-hour urine output (10.0±3.7 mL/d vs. 6.8±1.5; p<0.05; n=11/8). However, there was no difference in sodium excretion during this period (1.9±0.5 eq/d vs. 1.7±0.1; p=0.14; n=11/7). Interestingly, 4 hours after intraperitoneal saline injection, CD4^Arrb1-null mice excreted significantly less sodium compared to WT (5.6±3.5% vs. 31.4±10.6%; p<0.05; n=4/5).
Conclusion: Contrary to our hypothesis, these data suggest that T-cell Arrbs do not protect against the hypertensive response to ANG II, but instead play a complicated role in the modulation of hydromineral balance and inflammation.