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Angiotensin receptor agonistic autoantibodies induce pre-eclampsia in pregnant mice.

ABSTRACT: Pre-eclampsia affects approximately 5% of pregnancies and remains a leading cause of maternal and neonatal mortality and morbidity in the United States and the world. The clinical hallmarks of this maternal disorder include hypertension, proteinuria, endothelial dysfunction and placental defects. Advanced-stage clinical symptoms include cerebral hemorrhage, renal failure and the HELLP (hemolysis, elevated liver enzymes and low platelets) syndrome. An effective treatment of pre-eclampsia is unavailable owing to the poor understanding of the pathogenesis of the disease. Numerous recent studies have shown that women with pre-eclampsia possess autoantibodies, termed AT(1)-AAs, that bind and activate the angiotensin II receptor type 1a (AT(1) receptor). We show here that key features of pre-eclampsia, including hypertension, proteinuria, glomerular endotheliosis (a classical renal lesion of pre-eclampsia), placental abnormalities and small fetus size appeared in pregnant mice after injection with either total IgG or affinity-purified AT(1)-AAs from women with pre-eclampsia. These features were prevented by co-injection with losartan, an AT(1) receptor antagonist, or by an antibody neutralizing seven-amino-acid epitope peptide. Thus, our studies indicate that pre-eclampsia may be a pregnancy-induced autoimmune disease in which key features of the disease result from autoantibody-induced angiotensin receptor activation. This hypothesis has obvious implications regarding pre-eclampsia screening, diagnosis and therapy.

SUBMITTER: Zhou CC

PROVIDER: S-EPMC3267158 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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Angiotensin receptor agonistic autoantibodies induce pre-eclampsia in pregnant mice.

Zhou Cissy C CC Zhang Yujin Y Irani Roxanna A RA Zhang Hong H Mi Tiejuan T Popek Edwina J EJ Hicks M John MJ Ramin Susan M SM Kellems Rodney E RE Xia Yang Y

Nature medicine 20080727 8

Pre-eclampsia affects approximately 5% of pregnancies and remains a leading cause of maternal and neonatal mortality and morbidity in the United States and the world. The clinical hallmarks of this maternal disorder include hypertension, proteinuria, endothelial dysfunction and placental defects. Advanced-stage clinical symptoms include cerebral hemorrhage, renal failure and the HELLP (hemolysis, elevated liver enzymes and low platelets) syndrome. An effective treatment of pre-eclampsia is unava ...[more]

PMID: 18660815

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Project description:ImportanceAngiotensin II is significantly associated with the pathogenesis of acute aortic dissection. Angiotensin II type 1 receptor agonistic autoantibodies (AT1-AAs) can mimic the effect of angiotensin II.ObjectiveTo investigate the association between AT1-AAs and all-cause and cause-specific mortality risk in patients with acute aortic dissection.Design, setting, and participantsA total of 662 patients with clinically suspected aortic dissection from 3 medical centers in Wuhan, China, were enrolled in this cohort study from August 1, 2014, to July 31, 2016. Of these, 315 patients were included in the 3-year follow-up study. Follow-up was mainly performed via telephone interviews and outpatient clinic visits. Data analysis was conducted from March 1 to May 31, 2020.Main outcomes and measuresThe primary outcomes of interest were all-cause mortality, death due to aortic dissection, and late aortic-related adverse events.ResultsThe full study cohort included 315 patients with AAD (mean [SD] age, 56.2 [12.7] years; 230 men [73.0%]). Ninety-two patients (29.2%) were positive for AT1-AAs. The mortality of AT1-AA-positive patients was significantly higher than that of AT1-AA-negative patients (40 [43.5%] vs 37 [16.6%]; P < .001). The mortality risk in AT1-AA-positive patients was always significantly higher than that in AT1-AA-negative patients in patients with both type A and type B dissection. Multivariable analysis showed that the risk of AT1-AA-positive patients for type A dissection was significantly higher than that of AT1-AA-negative patients (odds ratio [OR], 1.88; 95% CI, 1.12-3.13; P = .02). The Cox proportional hazards regression model showed a significant increase of all-cause mortality risk (OR, 2.27; 95% CI, 1.44-3.57; P < .001) and late aortic-related adverse events (OR, 1.58; 95% CI, 1.06-2.36; P = .03) among AT1-AA-positive patients during the follow-up period compared with AT1-AA-negative patients.Conclusions and relevanceThis cohort study first detected AT1-AAs in patients with acute aortic dissection. The presence of AT1-AAs was associated with significantly higher all-cause and cause-specific mortality during a follow-up period of 3 years. The antibodies may be a risk factor for aortic dissection.

Project description:Background Agonistic autoantibodies against the angiotensin II type 1 receptor (AT1-AAs) extensively exist in patients with hypertensive diseases and have been demonstrated to play crucial roles in the pathophysiological process of vascular remodeling. However, the treatment options are limited. The large-conductance calcium-activated potassium (BK) channel is a critical regulator and potential therapeutic target of vascular tone and architecture. We have previously observed that AT1-AAs have an inhibitory effect on BK channels. However, whether BK channel dysfunction is involved in AT1-AAs-induced vascular remodeling and the therapeutic effect of BK channel opener is unclear. Methods and Results In our study, mesenteric arteries from AT1-AAs-positive rats exhibited increased wall thickness, narrowing of the arteriolar lumen, and increased collagen accumulation. Patch clamp test results showed that the voltage sensitivity of BK channel declined in mesenteric arteriolar smooth muscle cells from AT1-AAs-positive rats. Experiments with freshly isolated mesenteric arteriolar smooth muscle cells showed that AT1-AAs reduced the opening probability, open levels, open dwell time, and calcium sensitivity of BK channel. Experiments with HEK293T cells transfected with GFP-ZERO-BK α-subunit plasmids suggested a BK channel α-subunit-dependent mechanism. BK channel α-subunit deficient, namely KCNMA1-/- rats showed a phenotype of mesenteric artery remodeling. The administration of NS1619, a specific BK channel opener targeting the α-subunit, reversed the phenotypic transition and migration induced by AT1-AAs in cultured mesenteric arteriolar smooth muscle cells. Finally, perfusion of NS1619 significantly relieved the pathological effects induced by AT1-AAs in vivo. Conclusions In summary, we provide compelling evidence that BK channel α-subunit dysfunction mediates AT1-AAs-induced mesenteric artery remodeling. Preservation of BK channel activity may serve as a potential strategy for the treatment of AT1-AAs-induced maladaptive resistance artery remodeling.

Project description:BackgroundPre-eclampsia is the leading cause of maternal and neonatal morbidity and mortality with incompletely understood etiopathogenesis. The purpose of the current study is to determine whether there is a relationship between the presence of autoantibodies against β1, β2 and α1 adrenoreceptors and severe pre-eclampsia.Methodology/principal findingsSynthetic peptides corresponding to amino acid sequences of the second extracellular loops of β1, β2 and α1 adrenoreceptors were synthesized as antigens to test 34 patients with severe pre-eclampsia, 36 normal pregnancy women and 40 non-pregnant controls for the presence of autoantibodies using enzyme-linked immunosorbent assay. The respective frequencies of autoantibodies against β1, β2 and α1 adrenoreceptors were 50.0% (17/34), 52.9% (18/34) and 55.9% (19/34) in patients with severe pre-eclampsia, 19.4% (7/36) (p = 0.011), 19.4% (7/36) (p = 0.006) and 17.6% (6/36) (p = 0.001) in normal pregnancy women and 10% (4/40), 7.5% (3/40) and 10% (4/40) (p<0.001) in non-pregnant controls. Titers of these autoantibodies were also significantly increased in patients with severe pre-eclampsia. By logistic regression analysis, the presence of these three autoantibodies significantly increased the risk of neonatal death (odds ratio, 13.5; 95% confidence interval, 1.3-141.3; p = 0.030) and long-term neonatal hospitalization (odds ratio, 5.0; 95% confidence interval, 1.3-19.1; p = 0.018). The risk of hypertension and fetal distress were also associated with the presence of these three autoantibodies.Conclusions/significanceThis novel pilot study demonstrated for the first time that the presence of autoantibodies against β1, β2 and α1 adrenoreceptors are increased in patients with severe pre-eclampsia. Pregnant women who are positive for the three autoantibodies are at increased risks of neonatal mortality and morbidity. We posit that these autoantibodies may be involved in the pathogenesis of severe pre-eclampsia.

Project description:BackgroundPre-eclampsia is the most common complication occurring during pregnancy. In the majority of cases, it is concurrent with other pathologies in a comorbid manner (frequent co-occurrences in patients), such as diabetes mellitus, gestational diabetes and obesity. Providing bronchial asthma, pulmonary tuberculosis, certain neurodegenerative diseases and cancers as examples, we have shown previously that pairs of inversely comorbid pathologies (rare co-occurrences in patients) are more closely related to each other at the molecular genetic level compared with randomly generated pairs of diseases. Data in the literature concerning the causes of pre-eclampsia are abundant. However, the key mechanisms triggering this disease that are initiated by other pathological processes are thus far unknown. The aim of this work was to analyse the characteristic features of genetic networks that describe interactions between comorbid diseases, using pre-eclampsia as a case in point.ResultsThe use of ANDSystem, Pathway Studio and STRING computer tools based on text-mining and database-mining approaches allowed us to reconstruct associative networks, representing molecular genetic interactions between genes, associated concurrently with comorbid disease pairs, including pre-eclampsia, diabetes mellitus, gestational diabetes and obesity. It was found that these associative networks statistically differed in the number of genes and interactions between them from those built for randomly chosen pairs of diseases. The associative network connecting all four diseases was composed of 16 genes (PLAT, ADIPOQ, ADRB3, LEPR, HP, TGFB1, TNFA, INS, CRP, CSRP1, IGFBP1, MBL2, ACE, ESR1, SHBG, ADA). Such an analysis allowed us to reveal differential gene risk factors for these diseases, and to propose certain, most probable, theoretical mechanisms of pre-eclampsia development in pregnant women. The mechanisms may include the following pathways: [TGFB1 or TNFA]-[IL1B]-[pre-eclampsia]; [TNFA or INS]-[NOS3]-[pre-eclampsia]; [INS]-[HSPA4 or CLU]-[pre-eclampsia]; [ACE]-[MTHFR]-[pre-eclampsia].ConclusionsFor pre-eclampsia, diabetes mellitus, gestational diabetes and obesity, we showed that the size and connectivity of the associative molecular genetic networks, which describe interactions between comorbid diseases, statistically exceeded the size and connectivity of those built for randomly chosen pairs of diseases. Recently, we have shown a similar result for inversely comorbid diseases. This suggests that comorbid and inversely comorbid diseases have common features concerning structural organization of associative molecular genetic networks.

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Angiotensin receptor agonistic autoantibodies induce pre-eclampsia in pregnant mice.

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Angiotensin receptor agonistic autoantibodies induce pre-eclampsia in pregnant mice.

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