AT1 receptor agonistic antibodies, hypertension, and preeclampsia

doi:10.1016/j.semnephrol.2004.07.006

Seminars in Nephrology

Volume 24, Issue 6, November 2004, Pages 571-579

https://doi.org/10.1016/j.semnephrol.2004.07.006 Get rights and content

Immunologic mechanisms and putatively circulating mediators of preeclampsia are not a new idea, but are nevertheless compelling. Here we review studies relating to the role of agonistic antibodies that bind the second extracellular loop of the angiotensin II (AII) AT1 receptor in the pathogenesis as well as a pathologic phenotype of this disorder, focusing on observations in our laboratory. These agonistic autoantibodies (AT1-AA) appear with the development of preeclampsia and mostly are gone by 6 weeks after delivery. We have purified AT1-AA and have shown that they belong to the immunoglobulin (Ig)G3 subclass. We have shown their specificity by Western blotting, colocalization, and coimmunoprecipitation experiments. AT1-AA induce signaling in vascular cells and trophoblasts including activating protein-1 (AP-1) and nuclear factor κ B (NF-κΒ) activation. The signaling results in tissue factor production and reactive oxygen species generation, both of which have been implicated in preeclampsia. AT1-AA also signal via the calcineurin-nuclear factor of activated T cells and contribute to plasminogen activator inhibitor-1 (PAI-1) production and decreased trophoblast invasion. The role of AT1-AA in preeclampsia and other severe hypertensive conditions has not yet been proven with certainty. However, we believe the findings are compelling and warrant further study.

Section snippets

Initial observations

Our interest in circulating mediators and an important place for angiotensin II (AII) in the preeclampsia equation stem from early observations that platelets from preeclamptic women have increased intracellular free calcium (Ca_i²⁺) concentrations and that these concentrations increase even further with AII stimulation, but not with thrombin.3 The phenomenon disappears after delivery. These increments in intracellular calcium levels also have been observed by others.4 Our initial study involved

Evaluating the role of AII

In the face of earlier observations that women with preeclampsia are markedly hyperresponsive to circulating AII7 and the findings we had observed earlier in the platelets,3 we were encouraged to direct our attention specifically toward AII. However, AII levels had been studied in detail in preeclamptic women by other investigators. In general, circulating AII levels were normal or even below normal in these studies. Moreover, the findings indicated that in preeclampsia, the activity of the

Exploring the roles of AT1-AA

We were aware of the fact that the notion of circulating AT1-AA would evoke much skepticism. We had not shown that AT1-AA might induce changes that contributed to preeclampsia. We next embarked on cellular observations to test the notion that AT1-AA can evoke signaling in vascular cells that could contribute to preeclampsia. Women with preeclampsia have an accelerated thrombotic tendency particularly in placenta, and tissue factor has been implicated in this process. We decided to focus on

Exploring the roles of AT1-AA

Much remains unknown about the nature of AT1-AA, its receptor binding properties, and subsequent signaling. We focused on the ability of the AT1-AA to recognize a specific conformation of the AT1 receptor.14 Cleavage of the external disulfide bond with dithiothreitol caused an inactivation of the receptor when stimulated either with AII or the autoantibodies in cultured neonatal rat cardiomyocytes. Long-term stimulation of the AT1 receptor with either agonist down-regulated the AT1

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Regulation of vascular angiotensin II type 1 and type 2 receptor and angiotensin-(1–7)/MasR signaling in normal and hypertensive pregnancy
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Normal pregnancy (Norm-Preg) is associated with a slight reduction in blood pressure (BP) and decreased BP response to vasoconstrictor stimuli such as angiotensin II (Ang II), although the renin-angiotensin-aldosterone system (RAAS) is upregulated. Preeclampsia (PE) is a complication of pregnancy manifested as hypertension-in-pregnancy (HTN-Preg), and dysregulation of angiotensin biosynthesis and signaling have been implicated. Ang II activates vascular Ang II type-1 receptor (AT₁R) and Ang II type-2 receptor (AT₂R), while angiotensin-(1–7) promotes Ang-(1–7)/MasR signaling. The role of AT₁R in vasoconstriction and the activated cellular mechanisms are well-characterized. The sensitivity of vascular AT₁R to Ang II and consequent activation of vasoconstrictor mechanisms decrease during Norm-Preg, but dramatically increase in HTN-Preg. Placental ischemia in late pregnancy could also initiate the release of AT₁R agonistic autoantibodies (AT₁AA) with significant impact on endothelial dysfunction and activation of contraction pathways in vascular smooth muscle including [Ca²⁺]_c and protein kinase C. On the other hand, the role of AT₂R and Ang-(1–7)/MasR in vascular relaxation, particularly during Norm-Preg and PE, is less clear. During Norm-Preg, increases in the expression/activity of vascular AT₂R and Ang-(1–7)/MasR promote the production of endothelium-derived relaxing factors such as nitric oxide (NO), prostacyclin and endothelium-derived hyperpolarizing factor leading to generalized vasodilation. Aortic segments of Preg rats show prominent endothelial AT₂R staining and increased relaxation and NO production in response to AT₂R agonist CGP42112A, and treatment with AT₂R antagonist PD123319 enhances phenylephrine-induced contraction. Decreased vascular AT₂R and Ang-(1–7)/MasR expression and receptor-mediated mechanisms of vascular relaxation have been suggested in HTN-Preg animal models, but their role in human PE needs further testing. Changes in angiotensin-converting enzyme-2 (ACE2) have been observed in COVID-19 patients, and whether ACE2 influences the course of COVID-19 viral infection/immunity in Norm-Preg and PE is an intriguing area for research.
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Citation Excerpt :
More research is needed to confirm the findings of Aggarwal et al. (2017). AT1R-AA is functionally similar to AngII, and the latter could increase SNA through the AT1Rs in the CNS (Stein et al., 1984; Dechend et al., 2000, 2004, 2005, 2006; Ruzicka et al., 2013). Yet, there has been no evidence showing a direct central effect of AT1R-AA on sympathetic activity in animals or humans.
There is an increase in basal sympathetic nerve activity (SNA) during normal pregnancy; this counteracts profound primary vasodilation. However, pregnancy also impairs baroreflex control of heart rate and SNA, contributing to increased mortality secondary to peripartum hemorrhage. Pregnancy-induced hypertensive disorders evoke even greater elevations in SNA, which likely contribute to the hypertension. Information concerning mechanisms is limited. In normal pregnancy, increased angiotensin II acts centrally to support elevated SNA. Hypothalamic sites, including the subfornical organ, paraventricular nucleus, and arcuate nucleus, are likely (but unproven) targets. Moreover, no definitive mechanisms for exaggerated sympathoexcitation in hypertensive pregnancy have been identified. In addition, normal pregnancy increases gamma aminobutyric acid inhibition of the rostral ventrolateral medulla (RVLM), a key brainstem site that transmits excitatory inputs to spinal sympathetic preganglionic neurons. Accumulated evidence supports a major role for locally increased production and actions of the neurosteroid allopregnanolone as one mechanism. A consequence is suppression of baroreflex function, but increased basal SNA indicates that excitatory influences predominate in the RVLM. However, many questions remain regarding other sites and factors that support increased SNA during normal pregnancy and, more importantly, the mechanisms underlying excessive sympathoexcitation in life-threatening hypertensive pregnancy disorders such as preeclampsia.
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AT1 receptor agonistic antibodies, hypertension, and preeclampsia

Section snippets

Initial observations

Evaluating the role of AII

Exploring the roles of AT1-AA

Exploring the roles of AT1-AA

Am J Hypertens

Lancet

J Mol Cell Cardiol

Am J Hypertens

Renal and cardiovascular alterations

Pre-eclampsia and the maternal cardiovascular risk

Nephrol Dial Transplant

Increased intracellular free calcium and sensitivity to angiotensin II in platelets of preeclamptic women

Am J Hypertens

Endothelial adhesion molecules and leukocyte integrins in preeclamptic patients

Hypertension

A study of angiotensin II pressor response throughout primigravid pregnancy

J Clin Invest

Determination of renin, angiotensin converting enzyme and angiotensin II levels in human placenta, chorion and amnion from women with pregnancy induced hypertension

Clin Endocrinol

Immunohistochemical localization of angiotensin II receptors (AT1) in the heart with anti-peptide antibodies showing a positive chronotropic effect

Receptors Channels

Specific removal of beta1-adrenergic autoantibodies from patients with idiopathic dilated cardiomyopathy

N Engl J Med

Molecular mimicry between the immunodominant ribosomal protein P0 of Trypanosoma cruzi and a functional epitope on the human beta 1-adrenergic receptor

J Exp Med