Angiotensin II Type 1 Receptor Autoantibody (AT1-AA)-Mediated Pregnancy Hypertension


  • Florian Herse,

    Corresponding author
    • Experimental and Clinical Research Center, a joint cooperation between the Charité Medical Faculty and the Max-Delbrueck Center for Molecular Medicine, Berlin, Germany
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  • Babbette LaMarca

    1. Department of Obstetrics and Gynecology, University of Mississippi Medical Center, Mississippi, Jackson, USA
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Florian Herse, Experimental and Clinical Research Center (ECRC)

Lindenberger Weg 80, 13125 Berlin, Germany. E-mail:


Autoantibodies can cause complications in pregnancy. Preeclampsia is the leading cause of maternal and fetal morbidity and mortality during pregnancy. Overall, 5–10% of all pregnancies worldwide develop preeclampsia. Women who developed preeclampsia and their children have an increased risk to suffer from cardiovascular diseases later in life. In preeclampsia, agonistic autoantibodies against the angiotensin II type 1 receptor autoantibodies (AT1-AA) are described. They induce NADPH oxidase and the MAPK/ERK pathway leading to NF-κB and tissue factor activation. AT1-AA are detectable in animal models of preeclampsia and are responsible for elevation of soluble fms-related tyrosine kinase-1 (sFlt1) and soluble endoglin (sEng), oxidative stress, and endothelin-1, all of which are enhanced in preeclamptic women. AT1-AA can be detected in pregnancies with abnormal uterine perfusion and increased resistance index as well as in patients with systemic sclerosis and renal allograft rejection. This review discusses the current knowledge about the AT1-AA, its signaling, and their impact in pregnancy complications and other autoimmune disorders.

Autoantibodies appearing in pregnancy complications or diseases have been described for many years, including thyroid-stimulating autoantibodies, anti-Ro/SSA antibodies, and antiphospholipid antibodies.[1-3] Wallukat et al.[4] described 1999 autoantibodies against the angiotensin II type 1 (AT1) receptor autoantibody (AT1-AA) in pregnant women, developing new onset hypertertension, preeclampsia. Preeclampsia can be distinguished from other pregnancy-induced hypertension disorders by the criteria of the American College of Obstetricians and Gynecologists (ACOG). It is characterized by a new onset of blood pressure (>140/90 mmHg) and proteinuria (>300 mg/L) in a previously normotensive woman.[5] It is the leading cause of maternal and fetal morbidity and mortality. Overall, 5–10% of all pregnancies worldwide develop preeclampsia.[6] Women that developed preeclampsia and their children have an increased risk to suffer from cardiovascular diseases in later life.[7, 8] Currently, there is no adequate therapy available that takes into account both the mother and the child. This is due to the fact that the exact nature of the disease is unclear. It remains only a premature birth to protect the mother from severe damage such as intracranial bleeding or kidney damage.[9] Numerous risk factors have been linked to preeclampsia. Besides obesity, associations with autoimmune diseases, immunological factors, and genetic components have been described.[10] The renin–angiotensin system (RAS) has been implicated in the pathogenesis of preeclampsia.[11, 12] Besides dysregulation of the plasma renin concentration and renin activity, angiotensin II (Ang II) levels are increased during normal pregnancy, but vascular responsiveness to Ang II is decreased.[12] In contrast, preeclamptic patients are sensitive to Ang II, although the circulating Ang II concentrations are lower compared with control pregnancies.[12] A further dysregulation of the RAS during preeclamptic disease is the presence of the activating AT1-AA in the circulation of preeclamptic patients. Utilizing a cardiomyocyte contraction bioassay, the epitope of the AT1-AA has been identified in the second extracellular loop of the AT1-receptor and comprised the amino acids AFHYESQ. Confocal microscopy and co-immunoprecipitation confirmed the binding of the autoantibodies to the AT1-receptor.[4] Indicating that the AT1-AA are not specific for preeclampsia, Walther et al.[13] also described the AT1-AA in women with uneventful pregnancies and normotensive pregnant women with uterine growth-restricted fetuses. The combining parameter of all AT1-AA-positive women in this study was an abnormal uterine artery Doppler flow and increased resistance index. A pathological Doppler finding indicates impaired placentation in the context of uteroplacental hypoxia.[14] Furthermore, AT1-AA were also detected outside of pregnancy, namely in kidney transplant recipients who had refractory vascular rejection, patients with systemic sclerosis, featuring autoimmunity, vasculopathy, and tissue fibrosis, and patients with malignant secondary hypertension, mainly attributable to renovascular diseases.[15-17] All these patients share the abnormalities of hypertension, hypoxia, or vasculitis. The antibodies found in renal allograft rejection and malignant hypertension showed to have a second epitope in addition to those one found in preeclamptic women, whereas an epitope for systemic sclerosis is not described yet, but in this case, several other autoantibodies contribute to the complexity of disease.[18, 19] In patients with allograft rejection, plasmapheresis and treatment with AT1-receptor blocker prolonged the graft survival and improved renal function.[16] In hypertensive patients showing the AT1-AA, an AT1-receptor blocker-based therapy (candesartan) was able to lower blood pressure more efficiently than an ACE-inhibitor-based therapy (Imidapril) that was an adequate therapy in hypertensive patients without AT1-AA.[20] However, an AT1-receptor blocker therapy is not appropriate in pregnant women as the treatment leads to severe maldevelopment of the kidney in the fetus.[21-23]

Signal transduction of AT1-AA

The AT1-AA is an agonistic antibody that is able to activate the AT1-receptor similar to Ang II. Downstream of the AT1-receptor activation is the MAPK/ERK pathway. Dechend et al.[24] could show that the AT1-AA led to a phosphorylation of ERK1/2 in human coronary artery cells. Furthermore, the AP-1 and NF-kb binding site of the tissue factor (TF) were activated in these cells leading to an upregulated TF expression that is also present in preeclamptic placenta vessel walls. By formation of an enzymatic complex with the factor VII, the TF initiates coagulation cascade. An activated coagulation cascade and a reduced fibrinolytic capacity are described in the pathogenesis of preeclampsia.[25] The AT1-AA are also reported to induce the plasminogen activator inhibitor-1 (PAI-1), the most important physiological inhibitor of plasminogen, in trophoblast cells.[26] The invasiveness of trophoblasts is decreased after stimulation with AT1-AA.[27] PAI-1 is also upregulated in placentas of preeclamptic women, leading to a reduced fibrinolytic activity, which is also important for the extracellular matrix degradation by trophoblasts.[28]

Whether or not there is a hypoxic state in the preeclamptic placenta is controversially discussed. However, oxidative stress is largely described and contributes to the inflammation that can be found in placenta and circulation of preeclamptic women.[29-32] Vascular smooth muscle cells (VSMCs) and trophoblasts show an elevated ROS production, and the NADPH oxidase components, p22, p47, and p67 phox, are upregulated when stimulated by the AT1-AA. As a consequence, the NF-kb is activated, and the expression of their inhibitor, the I-κBα expression, was diminished.[33] These findings reflect the human situation, as in placentas from preeclamptic women, the p22, p47, and p67 phox expression and NF-κB activation are enhanced and I-κBα is reduced.[33]

IgG isolated from preeclamptic women activates the complement system in kidney and placenta when administered in mice during pregnancy. Wang et al.[34] could show that the deposition of C3 was mediated by the AT1-receptor and led to a preeclamptic phenotype. A dysregulation of the complement system is reported during the preeclamptic process.[35-37] Furthermore, in these animals, Cou et al. demonstrated the AT1-AA-exposed mice had elevated soluble fms-related tyrosine kinase-1 (sFlt1) and soluble Endoglin (sEng). This impaired placental angiogenesis is described as a cause of the AT1-AA-mediated tumor necrosis alpha (TNFα) induction.[38] The release of sFlt1 from preeclamptic placenta and the resulting imbalance of anti- and angiogenic factors are a possible working point for the discovery of biomarker or interventions in preeclampsia.[39, 40] Hubel et al.[41] could show that still 1 year after pregnancies, 17% of preeclamptic women showed circulating AT1-AA, whereas none in the control group. In the women with AT1-AA, sFlt1 was elevated and the circulating VEGF was lower, when compared with autoantibody-negative women. Unfortunately, Stepan et al.[42] could not detect a correlation between AT1-AA and sFlt1. They investigated women at gestational weeks 18–22 and compared women with abnormal uterine artery Doppler flow and increased resistance index to uneventful pregnancies and preeclamptic women at delivery to control women. Controversely, Siddiqui et al.[43] clearly demonstrate that the titer of AT1-AA not only correlates to the severity of the disease but that there was a strong correlation between AT1-AA activity and sFlt-1 in severe preeclamptics.

AT1-AA in animal models

The initiating event in preeclampsia is postulated to involve reduced utero placental perfusion (RUPP) that leads to hypertension by mechanisms not yet elucidated.[44, 45] Additionally, in recent years, a rodent animal model of RUPP, which displays many features most of preeclamptic cases, has been utilized to study the pathophysiology of the disease.[46, 47] Some of the most recent studies identify an important role for the AT1-AA to cause many of these preeclamptic characteristics.[48, 49] In a different animal model showing preeclamptic features, the AT1-AA also plays an important role. In this transgenic model, a female rat harboring the human angiotensinogen is mated by a male rat transgenic for the human renin. Besides albuminuria and hypertension, the AT1-AA is present.[50] Furthermore, transfer of the isolated rat AT1-AA or IgG from preeclamptic patients to pregnant rodents leads to preeclamptic phenotype. In detail, a chronic infusion of isolated rat AT1-AA in pregnant rats increased serum AT1-AA, blood pressure, and tissue levels of preproendothelin, an important endothelial-derived factor elevated in the plasma of preeclamptic women and thought to play a role in preeclampsia.[51] Renal endothelial dysfunction in these infused rats was mediated by the endothelin type A receptor.[52] Infusion of the AT1-AA also led to increased plasma sFlt1 and sEng level in pregnant rats.[53] Same findings were observed by Zhou et al.[54] in villous explant, cell culture, and pregnant mice. The purified AT1-AA induced a preeclamptic phenotype including hypertension, proteinuria, glomerular endotheliosis, placental abnormalities, and small fetus size and that was prevented by AT1-receptor antagonist and the peptide AFHYESQ.[55] A secondary phenomenon in preeclampsia is the increased sensitivity to Ang II.[56] This observation was explained by Wenzel et al.[57] using an autoimmune-activated receptor mediated by the AT1-AA.

Figure 1.

Signal cascades of the angiotensin II type 1 receptor autoantibodies (AT1-AA). The agonistic AT1-AA induces signaling by the angiotensin II type 1 receptor (AT1-receptor), blockable by AT1-receptor blocker (ARB) or the 7 aminoacid peptide (AFHYESQ) mimicking the epitope of the AT1-AA in the second extracellular domain of the AT1-receptor. Intracellular cascades and promoter activations in the nucleus lead to an upregulation of the tissue factor, soluble fms-like tyrosine kinase-1 (sFlt1), soluble endoglin (sEng), and endothelin-1 (ET-1).

AT1-AA and B cells

The AT1-AA was recently described to be produced by mature B cells. Jensen et al.[58] could show, that a specific B-cell type, the CD19(+)CD5(+) cells are responsible for AT1-AA production and only occur in preeclamptic placentas but not in placentas of normal pregnancies. For B-cell maturation and IgG production, several co-stimulatory signals must occur between the antibody-producing B lymphocyte and CD4+ T helper cells.[19, 20] Cross talk between these cells can be disturbed by inhibiting the CD20 receptor on the surface of the B cell[21, 22] This strategy was tested in the RUPP rat model to reduce the preeclamptic phenotype. The CD20 monoclonal antibody rituximab was able to reduce the B-cell population and thereby the AT1-AA, blood pressure, and endothelin production.[49] Additionally, adoptive transfer of CD4+ T cells isolated from RUPP rats to normal pregnant rats results in hypertension, elevated inflammatory cytokine (TNFα, IL-6), and AT1-AA production. Importantly, these soluble factors along with hypertension were also lowered by rituximab and AT1-AA suppression in the RUPP rat model of PE.[59]