AT1 receptor agonistic antibodies, hypertension, and preeclampsia

Immunologic mechanisms and putatively circulating mediators of preeclampsia are not a new idea, but are nevertheless compelling. Here we review studies relating to the role of agonistic antibodies that bind the second extracellular loop of the angiotensin II (AII) AT1 receptor in the pathogenesis as well as a pathologic phenotype of this disorder, focusing on observations in our laboratory. These agonistic autoantibodies (AT1-AA) appear with the development of preeclampsia and mostly are gone by 6 weeks after delivery. We have purified AT1-AA and have shown that they belong to the immunoglobulin (Ig)G3 subclass. We have shown their specificity by Western blotting, colocalization, and coimmunoprecipitation experiments. AT1-AA induce signaling in vascular cells and trophoblasts including activating protein-1 (AP-1) and nuclear factor kappa B (NF-kappaBeta) activation. The signaling results in tissue factor production and reactive oxygen species generation, both of which have been implicated in preeclampsia. AT1-AA also signal via the calcineurin-nuclear factor of activated T cells and contribute to plasminogen activator inhibitor-1 (PAI-1) production and decreased trophoblast invasion. The role of AT1-AA in preeclampsia and other severe hypertensive conditions has not yet been proven with certainty. However, we believe the findings are compelling and warrant further study.