The detrimental role of angiotensin receptor agonistic autoantibodies in intrauterine growth restriction seen in preeclampsia

Abstract

Growth-restricted fetuses are at risk for a variety of lifelong medical conditions. Preeclampsia, a life-threatening hypertensive disorder of pregnancy, is associated with fetuses who suffer from intrauterine growth restriction (IUGR). Recently, emerging evidence indicates that preeclamptic women harbor AT1 receptor agonistic autoantibodies (AT1-AAs) that contribute to the disease features. However, the exact role of AT1-AAs in IUGR and the underlying mechanisms have not been identified. We report that these autoantibodies are present in the cord blood of women with preeclampsia and retain the ability to activate AT1 receptors. Using an autoantibody-induced animal model of preeclampsia, we show that AT1-AAs cross the mouse placenta, enter fetal circulation, and lead to small fetuses with organ growth retardation. AT1-AAs also induce apoptosis in the placentas of pregnant mice, human villous explants, and human trophoblast cells. Finally, autoantibody-induced IUGR and placental apoptosis are diminished by either losartan or an autoantibody-neutralizing peptide. Thus, these studies identify AT1-AA as a novel causative factor of preeclampsia-associated IUGR and offer two possible underlying mechanisms: a direct detrimental effect on fetal development by crossing the placenta and entering fetal circulation, and indirectly through AT1-AA–induced placental damage. Our findings highlight AT1-AAs as important therapeutic targets.

Soluble fms-like tyrosine kinase 1 promotes angiotensin II sensitivity in preeclampsia

“…It would also be important to evaluate the effects of angiotensin receptor autoantibody (AT1-AA) in the context of high sFLT1. While suppression of circulating RAS is typical (63), there is ample evidence that AT1-AA is present in patients with preeclampsia (7,(64)(65)(66). We also do not know the mechanisms of ing that in preeclampsia, there is increased vascular sensitivity to other vasoconstrictors, this suggests it is unlikely that alterations in circulating renin or Ang II underlie the pathogenesis of hypertension in preeclampsia.…”

Role of Biomarkers in Early Detection of Preeclampsia

“…Therefore, a close association is thought to exist between accelerated AT 1 signalling and sFlt1 production. AT 1 -AA is detectable in foetal cord blood in PE pregnancies, which is suggestive of its usage as a foetal-side marker for evaluating IUGR and other foetal conditions [23].…”

A2B Adenosine Receptor–Mediated Induction of IL-6 Promotes CKD

“…The fibrotic areas stained in light blue were picked up on the digital images using a computerized densitometry (ImagePro Plus, version 6.0; Media Cybernetics, Silver Spring, MD) coupled to a microscope equipped with a digital camera as described. 50,51 The percentage of the fibrotic area relative to the whole area of the field was calculated (percent fibrosis area). The average densities of 10 areas per kidney were averaged, the SEM is indicated, and n ϭ 4 to 6 kidneys for each category.…”