Abstract 47: Angiotensin Receptor Agonistic Autoantibody Mediated Vascular Impairment via sFlt-1 Contributes to Decreased Aldosterone Production in Preeclampsia
Preeclampsia (PE) is a multi-system disorder of pregnancy characterized by high blood pressure and proteinuria. Despite high blood pressure, a decreased circulating level of aldosterone is associated with PE. The molecular mechanisms underlying reduced aldosterone production in PE are unknown. In the present study we demonstrate for the first time that reduced aldosterone levels in the sera of preeclamptic women could be associated with the presence of angiotensin II type 1 receptor agonistic autoantibody (AT1-AA) and elevated soluble Fms-like tyrosine kinase-1 (sFlt-1), two prominent factors related to the pathophysiology of PE. Using a well established adoptive transfer animal model of PE, we provide in vivo evidence that the injection of IgG from women with PE, but not IgG from normotensive pregnant women (NT-IgG), resulted in hypertension, proteinuria and a reduction in aldosterone production. The aldosterone level decreased from 1377±272 pg/ml to 544±92 pg/ml (p<0.05) in pregnant mice. These features were prevented by co-injection with an epitope peptide that blocks the antibody-mediated AT1 receptor (AT1R) activation. In contrast, injection of IgG from preeclamptic women into non-pregnant mice resulted in an increase in the adolsterone levels from 213±24 pg/ml to 615±48 pg/ml (p<0.05). These results indicate that maternal circulating autoantibody in preeclamptic women is a detrimental factor for decreased aldosterone production via AT1R activation in a pregnancy-dependent manner. Next, we found that circulating sFlt-1 was increased more in the autoantibody-injected pregnant mice compared to the NT-IgG injected mice (56.1±4.6 vs 21.87±6.4 ng/ml, p<0.05). Furthermore upon infusion of VEGF121, we saw a recovery in the circulating levels of aldosterone (from 544±92 to 1110±269 pg/ml, p<0.05). Collectively, these results suggest that AT1-AA-induced sFlt-1 elevation is a novel pathogenic mechanism that promotes vascular impairment in adrenal glands leading to decreased aldosterone production in PE. Overall, our findings reveal novel factors and signaling cascades involved in decreased aldosterone production that could reveal possible therapeutic interventions in the timely management of PE.
- © 2012 by American Heart Association, Inc.