Angiotensin II Type 1 Receptor Autoantibodies Research Articles

Non-HLA angiotensin-type-1 receptor autoantibodies mediate the long-term loss of grafted neurons in Parkinson’s disease models

BackgroundClinical trials have provided evidence that transplants of dopaminergic precursors, which may be replaced by new in vitro stem cell sources, can integrate into the host tissue, and alleviate motor symptoms in Parkinson´s disease (PD). In some patients, deterioration of graft function occurred several months after observing a graft-derived functional improvement. Rejection of peripheral organs was initially related to HLA-specific antibodies. However, the role of non-HLA antibodies is now considered also relevant for rejection. Angiotensin-II type-1 receptor autoantibodies (AT1-AA) act as agonists of the AT1 receptors. AT1-AA are the non-HLA antibodies most widely associated with graft dysfunction or rejection after transplantation of different solid organs and hematopoietic stem cells. However, it is not known about the presence and possible functional effects of AT1-AA in dopaminergic grafts, and the effects of treatment with AT1 receptor blockers (ARBs) such as candesartan on graft survival.MethodsIn a 6-hydroxydopamine PD rat model, we studied the short-term (10 days)- and long-term (3 months) effects of chronic treatment with the ARB candesartan on survival of grafted dopaminergic neurons and microglial graft infiltration, as well as the effects of dopaminergic denervation and grafting on serum and CSF AT1-AA levels. The expression of AT1 receptors in grafted neurons was determined by laser capture microdissection.ResultsAt the early period post-grafting, the number of grafted dopaminergic neurons that survived was not significantly different between treated and untreated hosts (i.e., control rats and rats treated with candesartan), probably because, just after grafting, other deleterious factors are predominant for dopaminergic cell death, such as mechanical trauma, lack of growth factors/nutrients and ischemia. However, several months post-grafting, we observed a significantly higher number of surviving dopaminergic neurons and a higher density of striatal dopaminergic terminals in the candesartan-treated group. For several months, grafted rats showed blood and cerebrospinal fluid levels of AT1-AA higher than normal controls, and also higher AT1-AA levels than non-grafted parkinsonian rats.ConclusionsThe results suggest the use of ARBs such as candesartan in PD patients, particularly before and after dopaminergic grafts, and the need to monitor AT1-AA levels in PD patients, particularly in those candidates for dopaminergic grafting.

AT1R autoantibody promotes phenotypic transition of smooth muscle cells by activating AT1R-OAS2

Phenotypic transition of vascular smooth muscle cells (VSMCs) is an early event in the onset and progression of several cardiovascular diseases. As an important mediator of the renin-angiotensin system (RAS), activation of the angiotensin II type 1 receptor (AT1R) induces phenotypic transition of VSMCs. AT1R autoantibodies (AT1-AAs), which are agonistic autoantibodies of AT1R, have been detected in the sera of patients with a variety of cardiovascular diseases associated with phenotypic transition. However, the effect of AT1-AA on phenotypic transition is currently unknown. In this study, AT1-AA-positive rat model was established by active immunization to detect markers of VSMCs phenotypic transition. The results showed that AT1-AA-positive rats showed phenotypic transition of VSMCs, which was evidenced by the decrease of contractile markers, while the increase of synthetic markers in the thoracic aorta. However, in AT1-AA-positive AT1R knockout rats, the phenotypic transition-related proteins were not altered. In vitro, after stimulating human aortic smooth muscle cells with AT1-AA for 48 h, 2′-5′ oligoadenylate synthase 2 (OAS2) was identified as the key differentially expressed gene by RNA sequencing and bioinformatics analysis. Furthermore, high expression of OAS2 was found in aorta of AT1-AA-positive rats; knockdown of OAS2 by siRNA can reverse the phenotypic transition of VSMCs induced by AT1-AA. In summary, this study suggests that AT1-AA can promote phenotypic transition of VSMCs through AT1R-OAS2 pathway, and OAS2 might serve as a potential therapeutic target to prevent pathological phenotypic transition of smooth muscle cells.

Relationship between β1-AA and AT1-AA and Cardiac Function in Patients with Hypertension Complicated with Left Ventricular Diastolic Function Limitation.

To investigate the association between β1 adrenergic receptor autoantibodies (β1-AA) and angiotensin II type-1 receptor autoantibodies (AT1-AA) and cardiac function in patients with hypertension complicated with left ventricular diastolic function limitation. A total of 120 patients with essential hypertension who were not taking drug treatment and were hospitalised in the Department of Cardiology at the authors' hospital from April 2018 to December 2018 were enrolled in this study and divided into a diastolic dysfunction group (65 cases) and a normal diastolic group (55 cases) according to their left ventricular diastolic function. The levels of cardiac parameters, β1-AA, AT1-AA, and other indicators were compared. Logistic regression analysis was used to analyse the related factors affecting left ventricular diastolic dysfunction (LVDD). The diagnostic efficacy of related factors in the diagnosis of diastolic dysfunction was evaluated. Univariate analysis demonstrated that the left ventricular posterior wall diameter (10.29 ± 1.23 vs. 9.12 ± 1.53), left ventricular systolic dysfunction (10.56 ± 1.37 vs. 9.43 ± 1.44), systolic blood pressure (152.37 ± 10.24 vs. 140.33 ± 5.99), diastolic blood pressure (95.66 ± 6.34 vs. 87.33 ± 7.28), β1-AA (33 vs. 9 cases), and AT1-AA (35 cases vs. 12 cases) were higher in the dysfunction group than in the control group (all P < 0.05). Multivariate regression analysis showed that β1-AA (odds ratio (OR) = 1.96, 95% confidence interval (CI): 1.369-4.345) and AT1-AA (OR = 2.02, 95% CI: 1.332-6.720) were independent risk factors for cardiac diastolic dysfunction (P < 0.05). Both autoimmune antibodies had a certain predictive value, and the combined prediction value of the two was the highest, with an area under the curve of 0.942 (95% CI: 0.881~0.985). The positive rate of β1-AA and AT1-AA in essential hypertension patients with LVDD was higher than that in the normal group. Both β1-AA and AT1-AA could be used as early markers of LVDD in essential hypertension patients.

Abstract 13769: AT1R Autoantibody Levels Are Elevated in Patients Who Required Immunosuppression Escalation in Immune Checkpoint Inhibitor Mediated Myocarditis

Intro: Angiotensin-II (Ang-II) plays an important role in the pathophysiology of various cardiovascular disorders, including cardiomyopathy and hypertension. Angiotensin II type 1 receptor (AT1R) mediates the deleterious effects of Ang-II and can cause vasoconstriction, vascular and cardiac remodeling, and cell death. Animal models have shown that the AT1R signal is obligatory for the development of virus-induced myocardial injury through the proinflammatory action of Ang-II. Data from animal studies and human case studies showed AT1R autoantibodies (AT1R A) were a novel mediator of vasomotor changes and LV dysfunction related to acute myocarditis and that blocking AT1R can be effective. Hypothesis: Little is known whether patients on immune checkpoint inhibitors (ICI) develop AT1R A and whether this can worsen the severity of ICI myocarditis. We measured AT1R A in 9 hospitalized patients who were diagnosed with ICI induced myocarditis. We describe this cohort, the course of their illness and their response to steroids. Methods: This was a prospective study. Quantitative antibodies to AT1R at the time of hospitalization were measured by an Enzyme Linked Immunosorbent Assay (ELISA) (One Lambda) and classified as positive (&gt;17U/mL); at risk (10-17 U/mL) and negative (&lt;10 U/mL). Results: Demographic and co-morbidity details are shown (Table 1). 5/9 patients (55%) were either positive or at risk for AT1R A elevation. 4/9 patients (45%) were AT1R A negative. 4/5 (80%) of the AT1R A positive/at risk required increased immunosuppression whereas 1/4 (25%) of the AT1R A negative required increased immunosuppression for myocarditis. Conclusions: AT1R autoantibodies may worsen the severity of ICI myocarditis. A larger cohort study and comparisons of AT1R A levels in non-ICI patients are underway. If trends hold true, testing for AT1R A and treating with an angiotensin receptor blocker may be a potential strategy to reduce ICI myocarditis severity.

Abstract 14401: Elevated Levels of Angiotensin II Type 1 Receptor Autoantibodies Are Associated With Abnormal Echocardiogram Parameters in Women With Preeclampsia

Introduction: Preeclampsia (PEC) increases the long-term risk for heart failure with preserved ejection fraction (HFpEF). While the underlying pathogenesis is unknown, angiotensin II type 1 receptor autoantibodies (AT1-AA) have been implicated. AT1-AA bind agonistically to the AT1 receptor and may result in clinical manifestations of preeclampsia. We aimed to determine whether women with PEC have elevated AT1-AA levels compared to normotensive women (controls) during pregnancy and at 4 years postpartum, and whether AT1-AA levels correlate with abnormal echocardiographic parameters. Methods: We performed a prospective longitudinal cohort study comparing women with PEC (n=21) to controls (n=20). AT1-AA and echocardiographic measurements were obtained during pregnancy and 4 years postpartum. Linear regression analyses were performed to evaluate the association between AT1-AA levels and important echocardiographic parameters. Results: Mean AT1-AA level during pregnancy differed significantly between women with PEC versus healthy pregnant controls (10.21±3.20 vs 6.33±3.40 μg/ml, p&lt;0.001). Women with PEC were more likely to be black and deliver at an earlier gestational age. Higher AT1-AA was associated with increased systolic/diastolic blood pressure, echocardiographic markers of biventricular systolic function (tricuspid annular systolic plane excursion and left ventricular (LV) ejection fraction), concentric LV hypertrophy and worsened diastolic function. AT1-AA remained persistently elevated at 4 years in women with PEC at baseline compared to controls (12.76±5.13 vs 4.47±1.49 μg/ml, p&lt;0.001) (Figure 1). Conclusions: Women with PEC have elevated AT1-AA compared to controls, both during pregnancy and 4 years postpartum. Higher AT1-AA is associated with abnormal diastolic parameters, LV remodeling, and hyperdynamic biventricular function. These findings suggest that AT1-AA plays an important role in the risk of HFpEF in PEC.

AT1-receptor autoantibody exposure contributes to cardiac dysfunction and increased glycolysis in fetal mice

Abstract Exposure to adverse factors in utero may lead to adaptive changes in cardiac structure and metabolism, which increases the risk of chronic cardiovascular disease later in life. Studies showed that the angiotensin II type 1 receptor autoantibodies (AT1-AAs) are able to cross the placenta into the circulation of pregnant rodents’ embryo, which adversely affects embryogenesis. However, the effects of AT1-AA exposure on the fetal heart in utero are still unknown. In this study, we investigated whether intrauterine AT1-AA exposure has adverse effects on fetal heart structure, function and metabolism. AT1-AA-positive pregnant mouse models were successfully established by passive immunity, evidenced by increased AT1-AA content. Morphological and ultrasonic results showed that the fetal mice on embryonic day 18 (E18) of AT1-AA group have loose and disordered myocardial structure, and decreased left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), compared with control groups. The myocardium of AT1-AA group fetal mice on E18 exhibited increased expression of the key molecules in the glycolytic pathway, pyruvate and lactic acid content and ATP production, suggesting that the glycolysis rate was enhanced. Furthermore, the enhanced effect of glycolysis caused by AT1-AA is mainly through the PPARβ/δ pathway. These data confirmed that fetus exposure to AT1-AA in utero developed left ventricular dysfunction, myocardial structural arrangement disorders, and enhanced glycolysis on E18. Our results support AT1-AA being a potentially harmful factor for cardiovascular disease in fetal mice.

AT1AA (Angiotensin II Type-1 Receptor Autoantibodies): Cause or Consequence of Human Primary Aldosteronism?

AT1AA (Angiotensin II type-1 receptor autoantibodies) were first detected in patients with primary aldosteronism (PA) because of aldosterone-producing adenoma (APA) with an in-house developed assay, but it remained unclear if they can be ascertained also with commercially available assays and if they have a functional role. Aims of our study were to investigate if (1) commercially available kits allow detection of raised AT1AA titer in APA; (2) this titer is normalized by adrenalectomy; and (3) AT1AA display any biological roles in vitro. We measured with 2 ELISA kits the AT1AA titer in serum of APA patients and its changes after adrenalectomy. We also investigated AT1AA bioactivity by using AT1-R (angiotensin type-1 receptor)-transfected Chinese hamster ovary and human adrenocortical carcinoma cells, and by measuring aldosterone synthase (CYP11B2) expression in human adrenocortical carcinoma cells after incubation with IgG. Both kits allowed detection of higher AT1AA levels in APA patients than in healthy subjects; surgical cure of PA did not decrease this titer at 1-month follow-up. Human adrenocortical carcinoma cells stimulation with IgG purified from sera of APA patients increased both CYP11B2 expression and aldosterone release (+40% and +76%, respectively, versus healthy subjects). However, no detectable effect of IgG was seen in Chinese hamster ovary cells expressing AT1-R. These findings support the contentions that (1) the raised AT1AA titer does not seem to be a consequence of hyperaldosteronism as it did not normalize after its cure; (2) AT1AA act as weak stimulators of aldosterone biosynthesis, but this effect can be identified only by using a sensitive in vitro technique.

The role of NO-cGMP pathway inhibition in vascular endothelial-dependent smooth muscle relaxation disorder of AT1-AA positive rats: protective effects of adiponectin

Angiotensin II type 1 receptor autoantibodies (AT1-AA) cause endothelial-dependent smooth muscle relaxation disorder. It is well understood that impairment of the NO–cGMP signaling pathway is one of the mechanisms of endothelial-dependent smooth muscle relaxation disorder. However, it is still unclear whether AT1-AA induces endothelial-dependent smooth muscle relaxation disorder via the impairment of the NO–cGMP signaling pathway. In addition, adiponectin exerts vascular endothelial protection through the NO–cGMP signaling pathway. Therefore, the purpose of this investigation was to assess the mechanism of vascular endothelial-dependent smooth muscle relaxation disorder induced by AT1-AA and the role of adiponectin in attenuating this dysregulation.Serum endothelin-1 (ET-1), adiponectin and AT1-AA were detected by enzyme-linked immunosorbent assay. In preeclamptic patients, there was an increased level of AT1-AA, which was positively correlated with ET-1 and negatively correlated with adiponectin, as elevated levels of ET-1 suggested endothelial injury. AT1-AA-positive animal models were actively immunized with the second extracellular loop of the angiotensin II type 1 receptor (AT1R-ECII) for eight weeks. In thoracic aortas of AT1-AA positive rats, ET-1 was elevated, endothelium-dependent vasodilation was decreased. Paradoxically, as the upstream element of the NO-cGMP signaling pathway, NO production was not decreased but increased, and the ratio of p-VASP/VASP, an established biochemical endpoint of NO-cGMP signaling pathway, was reduced. Moreover, the levels of nitrotyrosine and gp91phox which indicate the presence of peroxynitrite (ONOO-) and superoxide anion (O2·−) were increased. Pretreatment with the ONOO- scavenger FeTMPyP or O2·−scavenger Tempol normalized vasorelaxation. Key enzymes responsible for NO synthesis were also assessed. iNOS protein expression was increased, but p-eNOS(Ser1177)/eNOS was reduced. Preincubation with the iNOS inhibitor 1400 W or eNOS agonist nebivolol restored vasorelaxation. Further experiments showed levels of p-AMPKα (Thr172)/AMPKα, which controls iNOS expression and eNOS activity, to have been reduced. Furthermore, levels of the upstream component of AMPK, adiponectin, was reduced in sera of AT1-AA positive rats and supplementation of adiponectin significantly decreased ET-1 contents, improved endothelial-dependent vasodilation, reduced NO production, elevated p-VASP/VASP, inhibited protein expression of nitrotyrosine and gp91phox, reduced iNOS overexpression, and increased eNOS phosphorylation at Ser1177 in the thoracic aorta of AT1-AA positive rats.These results established that impairment NO–cGMP pathway may aggravate the endothelial-dependent smooth muscle relaxation disorder in AT1-AA positive rats and adiponectin improved endothelial-dependent smooth muscle relaxation disorder by enhancing NO–cGMP pathway. This discovery may shed a novel light on clinical treatment of vascular diseases associated with AT1-AA.

Evaluation of angiotensin II type-1 receptor antibodies in primary aldosteronism and further considerations about their possible pathogenetic role.

Angiotensin II type-1 receptor autoantibodies (AT1RAb) have been involved in the genesis of primary aldosteronism (PA), both in aldosterone-producing adenoma (APA) and in idiopathic hyperaldosteronism (IHA). In this study, we evaluated the titer of AT1RAb in 44 PA patients (15 with APA and 29 with IHA) compared with 18 normotensive healthy controls who were matched for gender and age. In 17 PA patients (6 APA and 11 IHA) the titer was evaluated under mineralocorticoid receptor (MR) antagonist treatment. We found that PA patients had a significantly higher titer of AT1RAb compared with controls (median values 33 [IQR 15.6] IU/mL vs 17.5 [IQR 10.8] IU/mL, respectively; P<0.0001). No significant difference of the AT1RAb titer was reported among PA patients, subdivided according to the subtypes and the concomitant MR antagonist therapy. No significant correlation was detected between age, gender, BMI, blood pressure values, baseline aldosterone, ARR, and the AT1RAb titer of all patients enrolled. Our data confirm an increased titer of AT1RAb in both subtypes of PA, independently from the concomitant use of MR antagonists and clinical/biochemical characteristics of PA patients. The small sample of patients and the relatively short time of treatment could have influenced these results. Moreover, the ELISA assay fails to evaluate the bioactivity of AT1RAb. Further studies should evaluate if the subtype, the clinical/biochemical recovery of PA, or both, influence the pathogenetic role of AT1RAb. The possible autoimmune pathogenesis and reversal effect with AT1R blocker treatment in PA patients with AT1RAb positivity is intriguing and requires further study.

Genetic and potential autoimmune triggers of primary aldosteronism.

Hypertension is a major life-threatening disease of high morbidity and mortality, which affects between 10% to 40% of the general population in an age-dependent manner. The pathogenesis of essential hypertension is multifactorial, with various underlying contributory mechanisms. Primary aldosteronism (PA) is the leading cause of secondary hypertension that affects 4.3% of patients in the general hypertensive population and 9.5% of patients referred to hypertension units.1 The 2 predominant causes of the constitutive aldosterone secretion that define PA is either aldosterone-producing adenomas (APA) or bilateral adrenal hyperplasia (BAH, also called idiopathic hyperaldosteronism). Exome sequencing has unraveled the pathogenetic basis of around half of APA, but the underlying cause of the aldosterone excess in BAH remains an enigma. The diagnosis of PA is made by a multistep process, recommended by the Endocrine Society guidelines,2 that ends with the invasive protocol of adrenal venous sampling. Once diagnosed, it is imperative to distinguish the surgically correctable forms (APA) from those that should be treated pharmacologically with mineralocorticoid receptor antagonists (BAH). With the application of wider screening for PA, >70% of cases of aldosterone excess have been defined as caused by BAH, with APA making up most of the remainder. APA and BAH are sporadic forms of PA, but 3 rarer familial forms of PA also exist called familial hyperaldosteronism (FH) types I, II, and III, described in more detail below. Three familial forms of PA with distinct clinical characteristics have been described.3,4 FH type I or glucocorticoid remediable aldosteronism is caused by a hybrid gene resulting from the unequal crossing-over between the adjacent genes CYP11B1 and CYP11B2 .5,6 Only few families (≈50) have been identified worldwide. FH type II seems to be inherited as an autosomal dominant trait. A locus has been mapped on chromosome 7p22 …

Prevalence of angiotensin II type 1 receptor (AT1R)–activating autoantibodies in primary aldosteronism

Autoantibodies to the angiotensin II type 1 receptor (AT1R) have been reported in patients with primary aldosteronism, including aldosterone producing adenoma (APA) and idiopathic adrenal hyperplasia (IAH). Sera from 25 primary aldosteronism subjects (12 with IAH and 13 with APA) and 15 normotensive control subjects were assayed for AT1R autoantibodies by enzyme–linked immunosorbent assay and an AT1R–transfected cell–based bioassay. Nine of 12 IAH subjects (75%) and six of 13 APA subjects (46%) were positive for AT1R autoantibodies in the bioactivity assay. The mean AT1R autoantibody activity for the IAH and APA subjects was significantly greater than controls (P < .001 and P < .01, respectively), and this in vitro activity was suppressed by the AT1R blocker losartan. None of the controls had significant AT1R autoantibody activity. Enzyme–linked immunosorbent assay values were less sensitive but were positive in some subjects with IAH and APA. The mean arterial pressure of these primary aldosteronism subjects correlated modestly with AT1R autoantibody activity. These data confirm the presence of active AT1R autoantibodies in a high percentage of subjects with primary aldosteronism irrespective of their underlying etiology. These observations have both pathophysiological and clinical implications.

A longitudinal study of circulating angiogenic and antiangiogenic factors and AT1-AA levels in preeclampsia

Our earlier studies of preeclampsia (PE) at delivery have demonstrated the alteration of one carbon cycle, reduced placental omega 3 fatty acids, altered circulating levels of angiogenic factors and differential placental gene-specific methylation patterns of angiogenic factors. This study was undertaken to examine changes in the levels of angiogenic factors and angiotensin II type 1 receptor autoantibodies (AT1-AAs) throughout gestation, from early pregnancy until delivery, in women with PE and to examine their association with cord angiogenic factors, blood pressure and infant weight. A total of 81 pregnant women (46 normotensive and 35 with PE) were followed at three different time points during pregnancy: 16-20 weeks (T1), 26-30 weeks (T2) and at the time of delivery (T3). The plasma levels of angiogenic factors and AT1-AAs were determined in the maternal and cord plasma by commercial enzyme-linked immunosorbent assay kits. Maternal plasma levels of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) were lower (P<0.05 for both), whereas soluble fms-like tyrosine kinase-1 (sFlt-1; P<0.05) and the sFlt-1/PlGF ratio (P<0.01) were higher in early pregnancy in the PE group. Maternal plasma AT1-AA levels were higher (P<0.05) at T2 in women with PE. Cord plasma VEGF and soluble kinase insert domain receptor (sKDR) levels were lower (P<0.01 and P<0.05, respectively), whereas AT1-AA levels were higher (P<0.05) in the PE group. Maternal plasma VEGF levels in early pregnancy were positively associated with systolic blood pressure, whereas the sFlt-1/PlGF ratio at T2 was negatively associated with infant weight in the PE group. Low levels of proangiogenic factors (VEGF and PlGF) and high levels of AT1-AAs and antiangiogenic factors (sFlt-1 and sFlt-1/PlGF ratio) are present in the maternal circulation during early gestation in women with PE.

The renin–angiotensin–aldosterone system in pre-eclampsia: the delicate balance between good and bad

Pregnancy demands major changes of the cardiovascular system, and this involves, among others, activation of the RAAS (renin-angiotensin-aldosterone system), allowing an aldosterone-dependent increase in volume. Remarkably, a relative resistance to the pressor response of AngII (angiotensin II) develops simultaneously to prevent the increase in blood pressure that would normally accompany RAAS activation. The increase in volume, the degree of RAAS activation and the diminished pressor response to AngII are less pronounced in pre-eclampsia. However, animal models displaying excessive RAAS activation also result in a pre-eclampsia-like syndrome, and the aldosterone/renin ratio is elevated in pre-eclampsia compared with a normal pregnancy. New insights into the pathogenesis of pre-eclampsia have revealed a major role for VEGF (vascular endothelial growth factor), VEGF-inactivating sFlt-1 (soluble fms-like tyrosine kinase-1) and AT1 (angiotensin II type 1) receptor autoantibodies. The last mentioned activate AT(1) receptors, thereby potentially suppressing circulating renin and aldosterone. VEGF, both directly and indirectly (by increasing capillary density), affects adrenal aldosterone synthesis. The present review summarizes all of the recent findings regarding RAAS regulation in pre-eclampsia compared with normal pregnancy, concluding that factors such as sFlt-1 and AT(1) receptor autoantibodies disturb the delicate balance that normally results in a volume increase and a diminished vasoconstrictor response to AngII in pregnant women. It is possible that there are non-parallel changes in the circulating and renal RAAS in pre-eclampsia, which are potentially reflected by the urinary levels of renin.

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

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.