Activating auto-antibodies against the AT1 receptor in preeclampsia

Dechend, Ralf; Müller, Dominik N.; Wallukat, Gerd; Homuth, Volker; Krause, Manja; Dudenhausen, Joachim W.; Luft, Friedrich C.

doi:10.1016/j.autrev.2004.07.002

Cited by 50 publications

(25 citation statements)

References 36 publications

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“…Two additional novel mechanisms of ANG receptor binding leading to contrasting effects have been recently demonstrated (1,140,141,756). First, AbdAlla et al (1) reported that the AT 2 receptor can directly bind to the AT 1 receptor and thereby antagonizes the function of AT 1 .…”

Section: Angiotensin Receptorsmentioning

confidence: 96%

Physiology of Local Renin-Angiotensin Systems

Paul

Mehr²,

Kreutz³

2006

Physiological Reviews

1,512

1,371

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Since the first identification of renin by Tigerstedt and Bergmann in 1898, the renin-angiotensin system (RAS) has been extensively studied. The current view of the system is characterized by an increased complexity, as evidenced by the discovery of new functional components and pathways of the RAS. In recent years, the pathophysiological implications of the system have been the main focus of attention, and inhibitors of the RAS such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin (ANG) II receptor blockers have become important clinical tools in the treatment of cardiovascular and renal diseases such as hypertension, heart failure, and diabetic nephropathy. Nevertheless, the tissue RAS also plays an important role in mediating diverse physiological functions. These focus not only on the classical actions of ANG on the cardiovascular system, namely, the maintenance of cardiovascular homeostasis, but also on other functions. Recently, the research efforts studying these noncardiovascular effects of the RAS have intensified, and a large body of data are now available to support the existence of numerous organ-based RAS exerting diverse physiological effects. ANG II has direct effects at the cellular level and can influence, for example, cell growth and differentiation, but also may play a role as a mediator of apoptosis. These universal paracrine and autocrine actions may be important in many organ systems and can mediate important physiological stimuli. Transgenic overexpression and knock-out strategies of RAS genes in animals have also shown a central functional role of the RAS in prenatal development. Taken together, these findings may become increasingly important in the study of organ physiology but also for a fresh look at the implications of these findings for organ pathophysiology.

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Section: Angiotensin Receptorsmentioning

confidence: 96%

Physiology of Local Renin-Angiotensin Systems

Paul

Mehr²,

Kreutz³

2006

Physiological Reviews

1,512

1,371

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“…The effect of vitamin D on AT1-AA in RUPP rats was quantified using the rat neonatal cardiomyocyte assay, as previously described (16,17,64). Briefly, AT1-AA was isolated by epitope binding and column purification from total IgG and chronotropic responses were measured and expressed as beats per minute.…”

Section: Methodsmentioning

confidence: 99%

Vitamin D supplementation improves pathophysiology in a rat model of preeclampsia

Faulkner

Cornelius

Amaral

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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Deficiency of vitamin D (VD) is associated with preeclampsia (PE), a hypertensive disorder of pregnancy characterized by proinflammatory immune activation. We sought to determine whether VD supplementation would reduce the pathophysiology and hypertension associated with the reduced uterine perfusion pressure (RUPP) rat model of PE. Normal pregnant (NP) and RUPP rats were supplemented with VD2 or VD3 (270 IU and 15 IU/day, respectively) on gestation days 14 -18 and mean arterial pressures (MAPs) measured on day 19. MAP increased in RUPP to 123 Ϯ 2 mmHg compared with 102 Ϯ 3 mmHg in NP and decreased to 113 Ϯ 3 mmHg with VD2 and 115 Ϯ 3 mmHg with VD3 in RUPP rats. Circulating CD4ϩ T cells increased in RUPP to 7.90 Ϯ 1.36% lymphocytes compared with 2.04 Ϯ 0.67% in NP but was lowered to 0.90 Ϯ 0.19% with VD2 and 4.26 Ϯ 1.55% with VD3 in RUPP rats. AT1-AA, measured by chronotropic assay, decreased from 19.5 Ϯ 0.4 bpm in RUPPs to 8.3 Ϯ 0.5 bpm with VD2 and to 15.4 Ϯ 0.7 bpm with VD3. Renal cortex endothelin-1 (ET-1) expression was increased in RUPP rats (11.6 Ϯ 2.1-fold change from NP) and decreased with both VD2 (3.3 Ϯ 1.1-fold) and VD3 (3.1 Ϯ 0.6-fold) supplementation in RUPP rats. Plasma-soluble FMS-like tyrosine kinase-1 (sFlt-1) was also reduced to 74.2 Ϯ 6.6 pg/ml in VD2-treated and 91.0 Ϯ 16.1 pg/ml in VD3-treated RUPP rats compared with 132.7 Ϯ 19.9 pg/ml in RUPP rats. VD treatment reduced CD4ϩ T cells, AT1-AA, ET-1, sFlt-1, and blood pressure in the RUPP rat model of PE and could be an avenue to improve treatment of hypertension in response to placental ischemia. hypertension; immune activation; preeclampsia; vitamin D PREECLAMPSIA (PE) IS A CLINICAL condition occurring in up to 7% of pregnancies in the United States commonly manifesting in late gestation (Ͼ20 wk gestation) with hypertension, placental ischemia, and low birth weight (5,27,47,48,58). Current treatment strategies for preeclampsia are targeted at safely lowering blood pressure and alleviating maternal complications (5, 48). PE pregnancies are characterized by an abnormal immune profile compared with that seen in normal pregnancies. PE women exhibit an altered immune balance favoring proinflammatory factors, such as CD4ϩ T cells, B cells, inflammatory cytokines, and autoantibodies to the angiotensin type 1 receptor (AT 1 -AA), which are known to stimulate production of antiangiogenic protein-soluble FMS-like tyrosine kinase-1 (sFlt-1) (18,33,34,56,57). In contrast, anti-inflammatory T regulatory cells (TREGs) are decreased in PE (22,53,56). These immune alterations are recapitulated in the established experimental model of PE, the reduced uterine perfusion pressure (RUPP) rat (1,20,21). Adoptive transfer of CD4ϩ T cells from RUPP rats induces hypertension, AT 1 -AA, inflammatory cytokines and sFlt-1, and endothelin-1 (ET-1) in normal pregnant rats, indicating the significant role these cells play in the pathogenesis of this disease (63). Furthermore, AT 1 -AA and sFlt-1 play a significant role in the development of endothelial dysfunction and hyp...

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“…63,64 It is difficult to argue that these are the specific cause of the syndrome even though the latter autoantibodies can generate a pre-eclampsialike disorder after administration to pregnant mice. 65 In a case-control study, we found that such antibodies were relatively common in normal pregnancy controls and not present in a substantial minority of cases.…”

Section: Pre-eclampsia and Autoantibodiesmentioning

confidence: 99%

REVIEW ARTICLE: Immunology of Pre‐Eclampsia

Redman

Sargent

2010

American J Rep Immunol

612

486

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Citation Redman CWG, Sargent IL. Immunology of Pre‐eclampsia. Am J Reprod Immunol 2010Pre‐eclampsia develops in stages, only the last being the clinical illness. This is generated by a non‐specific, systemic (vascular), inflammatory response, secondary to placental oxidative stress and not by reactivity to fetal alloantigens. However, maternal adaptation to fetal (paternal alloantigens) is crucial in the earlier stages. A pre‐conceptual phase involves maternal tolerization to paternal antigens by seminal plasma. After conception, regulatory T cells, interacting with indoleamine 2,3‐dioxygenase, together with decidual NK cell recognition of fetal HLA‐C on extravillous trophoblast may facilitate placental growth by immunoregulation. Complete failure of this mechanism would cause miscarriage, while partial failure would cause poor placentation and dysfunctional uteroplacental perfusion. The first pregnancy preponderance and partner specificity of pre‐eclampsia can be explained by this model. For the first time, the pathogenesis of pre‐eclampsia can be related to defined immune mechanisms that are appropriate to the fetomaternal frontier. Now, the challenge is to prove the detail.

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Activating auto-antibodies against the AT1 receptor in preeclampsia

Cited by 50 publications

References 36 publications

Physiology of Local Renin-Angiotensin Systems

Physiology of Local Renin-Angiotensin Systems

Vitamin D supplementation improves pathophysiology in a rat model of preeclampsia

REVIEW ARTICLE: Immunology of Pre‐Eclampsia

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