Angiotensin Receptor Agonistic Autoantibody Is Highly Prevalent in Preeclampsia

Abstract

Abstract-Preeclampsia (PE), a syndrome affecting 5% of pregnancies, characterized by hypertension and proteinuria, is a leading cause of maternal and fetal morbidity and mortality. The condition is often accompanied by the presence of a circulating maternal autoantibody, the angiotensin II type I receptor agonistic autoantibody (AT 1 -AA). However, the prevalence of AT 1 -AA in PE remains unknown, and the correlation of AT 1 -AA titers with the severity of the disease remains undetermined. We used a sensitive and high-throughput luciferase bioassay to detect AT 1 -AA levels in the serum of 30 normal, 37 preeclamptic (10 mild and 27 severe), and 23 gestational hypertensive individuals. Here we report that AT 1 -AA is highly prevalent in PE (Ϸ95%). Next, by comparing the levels of AT 1 -AA among women with mild and severe PE, we found that the titer of AT 1 -AA is proportional to the severity of the disease. Intriguingly, among severe preeclamptic patients, we discovered that the titer of AT 1 -AA is significantly correlated with the clinical features of PE: systolic blood pressure (rϭ0.56), proteinuria (rϭ0.70), and soluble fms-like tyrosine kinase-1 level (rϭ0.71), respectively. Notably, only AT 1 -AA, and not soluble fms-like tyrosine kinase-1, levels are elevated in gestational hypertensive patients. These data serve as compelling clinical evidence that AT 1 -AA is highly prevalent in PE, and its titer is strongly correlated to the severity of the disease. (Hypertension. 2010;55:386-393.)Key Words: preeclampsia Ⅲ gestational hypertension Ⅲ angiotensin receptor autoantibodies Ⅲ sFlt-1 Ⅲ proteinuria P reeclampsia (PE) is a serious hypertensive disorder of pregnancy that affects Ϸ5% of pregnancies and remains a leading cause of maternal and neonatal mortality and morbidity in the United States and the world. 1-3 The disease is multifactorial and includes such clinical features as high blood pressure, proteinuria, inflammation, endothelial dysfunction, vasoconstriction, and placental abnormalities. 4 -7 The clinical symptoms in the advanced stages of preeclampsia include cerebral hemorrhage, renal failure, hemolysis, elevated liver enzymes, and low platelets syndrome. In serious cases, termination of pregnancy is the only available option to prevent further deterioration of the fetus and mother. Despite being a leading cause of maternal death and a major contributor to maternal and perinatal morbidity, the triggering factors and underlying mechanisms responsible for the pathogenesis of PE remain elusive.Numerous studies have shown that women with PE possess angiotensin (Ang) II type 1 (AT 1 ) receptor agonistic autoantibodies (AAs) that bind to and activate the AT 1 Ang receptor in multiple cellular systems and provoke biological responses that are relevant to the pathophysiology of PE. 8 -13 For example, AT 1 -AAs increase the contraction rate of rat cardiomyocytes, elevate levels of the antiangiogenic factor soluble fms-like tyrosine kinase 1 (sFlt-1) leading to decreased angiogenesis in endothelial cells, in...

Vitamin D supplementation improves pathophysiology in a rat model of preeclampsia

“…Clinical data have confirmed that severe PE in patients is associated with higher circulating AT 1 -AA and sFlt-1 levels, demonstrating a link between these mediators and pathogenesis of the disease (59,60). This study is the first to measure changes in the production of AT 1 -AA and sFlt-1 in response to VD supplementation.…”

Preeclampsia: Updates in Pathogenesis, Definitions, and Guidelines

“…Furthermore, AT1-AA stimulates sFlt-1 and sEng by inducing TNF-a and overcoming its negative regulator, HO (59). In terms of human studies, Stepan et al (60) did not find a correlation between AT1-AA and sFlt-1 levels, whereas Siddiqui et al (61) did. Given these mixed results in humans, it remains questionable whether AT1-AA and sFlt-1 levels share the same pathophysiologic mechanism.…”

Towards biomarker-based tests that can facilitate decisions about prevention and management of preeclampsia in low-resource settings

“…Another 10 blood experimental biomarkers (AT-1AA [31], calcyclin, copeptin [34], galectin-1 [36], Gas6 [37], HIF-1aOH [38], IGFALS [41], mammalian HtrA3 [45], NT-proBNP [47], and PTX3 [49]), and four urine ones (C5b-9 [33], nephrin [46], iodine [42], and prolactin [52]) had limited clinical evaluation information, which impeded the evaluation of their performance for the diagnosis of PE. No clinical data were found for the remaining nine blood markers, which consisted of adipsin, α enolase, ADMA, Ba, 2,3-BPGM, Fetal DNA, marinobufagenin, plasma UA [51], and soluble CD117.…”