Abstract P089: Inhibition of AT1-AAs by Direct Binding Reduces Blood Pressure and Natural Killer Cell Activation in Response to Placental Ischemia of Pregnancy; Emphasizing the Importance of Novel Drug Development in the Treatment of Preeclampsia

Abstract

Preeclampsia (PE), hypertension with proteinuria during pregnancy, is associated with activating antibodies to the angiotensin II receptor (AT1-AA) and activation of cytolytic natural killer (NK) cells. The objective of our study was to determine if AT1-AA inhibition inhibits cytolytic NK cell activation in the reduced uterine perfusion pressure (RUPP) rat model of PE. We utilized a novel approach of specific epitope binding to inhibit AT1-AAs: AT1-AA inhibitory peptide (2ug/ml saline) was infused via miniosmotic pumps into RUPP rats beginning on day 14 of gestation. On day 19 of gestation, blood pressure (MAP) was measured and flow cytometry was performed to measure total and cytolytic NK cells in renal and placental tissues from all groups of rats.

MAP significantly increased from 87.1±6.2 in NP (n=5) to 125±2.3 in RUPP (n=6). Inhibition of AT1-AA by direct binding attenuated the hypertensive response to 74.9±19.02 mmHg in RUPP + AT1-AA inhibitor (n=3). Total renal NK cells measured at 10.21±3.69% in NP, 24.19±6.63% in RUPP, and 14.25±7.52% in RUPP + AT1-AA inhibitor. Total placental NK cells were 6.87±2.84% in NP (n=6), 27.62±10.97% in RUPP (N=6), and 6.35±3.90% in RUPP + AT1-AA inhibitor (N=5) rats. Importantly, activated cytolytic placental NK cells were significantly increased in NP (0.44±.24%) compared to RUPP (11.87±2.06%), and was blunted after epitope binding of AT1-AA in RUPP + AT1-AA inhibitor (2.33±1.02%, p<.0001 vs RUPP).

These studies indicate that AT1-AA inhibition improves maternal blood pressure and attenuates cytolytic activation of NK cells in response to placental ischemia, thereby emphasizing the importance of drug discovery for AT1-AA inhibition to improve pregnancy outcomes in preeclamptic patients.