Abstract P137: Knock Out Of Regulatory G Protein Signaling 2 Specifically In CD4 T Cells Prevents Angiotensin II Induced Hypertension

Abstract

Preeclampsia (PreE) is a hypertensive disorder in pregnancy. Aberrations of Regulator of G protein Signaling (RGS) family members are associated with PreE and hypertension (HTN). We previously observed a 9-fold increase in RGS2 in CD4+ T cells during PreE. In total, our work suggests that modulating T cells may be a therapeutic strategy for HTN. We hypothesize that reducing RGS2 specifically in CD4+ T cells will restore anti-inflammatory T cell responses and prevent HTN. Utilizing an angiotensin (ANG) II infusion mouse model, we aimed to investigate 1) the impact of the loss of RGS2 in CD4+ T cells on cytokine production and 2) if the loss of RGS2 in CD4+ T cells will protect against the development of HTN. RGS2 was knocked-out in CD4+ T cells (CD4-Cre x RGS2 flox mice; KO ). CD4 RGS2 KO (n=5) or littermate control mice (CTL, n=3) were administered 490 ng/kg/min ANG II for 21 days via mini-osmotic pump. Blood pressure was assessed by radiotelemetry. ELISAs were performed to determine pro- and anti- inflammatory cytokine levels in tissues from KO (n=9) and CTL (n=8) mice. Pro-inflammatory cytokines IFNγ and IL-17 were not significantly different in the heart, kidney, liver or spleen of KO vs CTL mice. The anti-inflammatory cytokines IL-4 (KO 410 vs CTL 339 pg/mL, p<0.05) and TGFβ (KO 5.7x10 5 vs 5.0x10 5 pg/mL, p<0.05) were increased in the kidneys of KO mice compared to CTL mice. At baseline, KO and CTL mice showed no differences in 24-hr heart rate (HR), systolic or diastolic blood pressure (SBP and DBP, respectively). Throughout the study, KO mice had a significantly lower 24-hr SBP (Day 7: KO 132.3 vs CTL 149.7 mmHg, p<0.05; Day 14: KO 123.6 vs CTL 162.3 mmHg, p<0.05; Day 21: KO 118.3 vs 154.8 mmHg, p<0.05) and DBP (Day 7: KO 101.2 vs CTL 113.8 mmHg, p<0.05; Day 14: KO 98.4 vs CTL 121.8 mmHg, p<0.05; Day 21: KO 96.8 vs 116.4 mmHg, p<0.05) compared to CTL mice. The 24-hr HR was only significantly lower at three weeks ANG II (KO 493.4 vs CTL 540.6 bpm, p<0.05) compared to CTL mice. The increased levels of IL-4 and TGFβ observed in KO mice support a role of RGS2 in anti-inflammatory immune responses. In accordance with our hypothesis, the loss of RGS2, specifically in CD4+ T cells prevented ANG II-induced hypertension. Therefore, RGS2 expression in CD4+ T cells plays a critical role in the development of HTN.