Angiotensin II type 1 receptor autoantibody as a novel regulator of aldosterone independent of preeclampsia

Yang, Jie; Li, L i; Shang, Jianyu; Cai, Lin; Song, Li; Zhang, Suli; Li, Hao; Li, Xiao; Ma, Xin‐Liang; Liu, Huirong

doi:10.1097/hjh.0000000000000521

Cited by 14 publications

(12 citation statements)

References 35 publications

(51 reference statements)

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“…228 The circulating levels of AT 1 -AA are also increased in RUPP compared with normal pregnant rats. 178,229–231 Also, infusion of AT 1 -AA in pregnant mice causes some of the manifestations of preeclampsia including increased blood pressure, proteinuria and increased plasma sFlt-1 levels.…”

Section: Circulating Bioactive Factors and Mmps In Preeclampsiamentioning

confidence: 95%

Matrix Metalloproteinases in Normal Pregnancy and Preeclampsia

Chen

Khalil

2017

Progress in Molecular Biology and Translational Science

229

168

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Normal pregnancy is associated with marked hemodynamic and uterine changes that allow adequate uteroplacental blood flow and uterine expansion for the growing fetus. These pregnancy-associated changes involve significant uteroplacental and vascular remodeling. Matrix metalloproteinases (MMPs) are important regulators of vascular and uterine remodeling. Increases in MMP-2 and MMP-9 have been implicated in vasodilation, placentation and uterine expansion during normal pregnancy. The increases in MMPs could be induced by the increased production of estrogen and progesterone during pregnancy. MMP expression/activity may be altered during complications of pregnancy. Decreased vascular MMP-2 and MMP-9 may lead to decreased vasodilation, increased vasoconstriction, hypertensive pregnancy and preeclampsia. Abnormal expression of uteroplacental integrins, cytokines and MMPs may lead to decreased maternal tolerance, apoptosis of invasive trophoblast cells, inadequate remodeling of spiral arteries, and reduced uterine perfusion pressure (RUPP). RUPP may cause imbalance between the anti-angiogenic factors soluble fms-like tyrosine kinase-1 and soluble endoglin and the pro-angiogenic vascular endothelial growth factor and placental growth factor, or stimulate the release of inflammatory cytokines, hypoxia-inducible factor, reactive oxygen species, and angiotensin AT1 receptor agonistic autoantibodies. These circulating factors could target MMPs in the extracellular matrix as well as endothelial and vascular smooth muscle cells, causing generalized vascular dysfunction, increased vasoconstriction and hypertension in pregnancy. MMP activity can also be altered by endogenous tissue inhibitors of metalloproteinases (TIMPs) and changes in the MMP/TIMP ratio. In addition to their vascular effects, decreases in expression/activity of MMP-2 and MMP-9 in the uterus could impede uterine growth and expansion and lead to premature labor. Understanding the role of MMPs in uteroplacental and vascular remodeling and function could help design new approaches for prediction and management of preeclampsia and premature labor.

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Section: Circulating Bioactive Factors and Mmps In Preeclampsiamentioning

confidence: 95%

Matrix Metalloproteinases in Normal Pregnancy and Preeclampsia

Chen

Khalil

2017

Progress in Molecular Biology and Translational Science

229

168

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“…AT 1 -AA is a bioactive factor that mediates its responses via AT 1 R. AT 1 -AA levels are elevated in serum of PE versus Norm-Preg women (Bai et al, 2013; Siddiqui et al, 2013) and further elevated in severe PE and in early than late PE (Yang et al, 2015). AT 1 -AA may enhance collagen-induced platelet aggregation, thus contributing to the hypercoagulability observed in PE (Bai et al, 2013).…”

Section: Circulating Bioactive Factors In Preeclampsiamentioning

confidence: 99%

“…In cultured trophoblasts, stimulation of AT 1 R with IgG isolated from PE women causes an increase in sFlt-1 levels (Zhou et al, 2008). Also, HUVECs treated with AT 1 -AA isolated from PE patients induces the release of lactate dehydrogenase (LDH) (Yang et al, 2014), a marker of both cellular death and necrosis, suggesting that AT 1 -AA may directly cause EC necrosis via AT 1 R activation. Also in HUVECs, AT 1 -AA induces the activity of caspase-3 and caspase-8, suggesting that it may promote EC apoptosis (Yang et al, 2014).…”

Section: Circulating Bioactive Factors In Preeclampsiamentioning

confidence: 99%

“…Also, HUVECs treated with AT 1 -AA isolated from PE patients induces the release of lactate dehydrogenase (LDH) (Yang et al, 2014), a marker of both cellular death and necrosis, suggesting that AT 1 -AA may directly cause EC necrosis via AT 1 R activation. Also in HUVECs, AT 1 -AA induces the activity of caspase-3 and caspase-8, suggesting that it may promote EC apoptosis (Yang et al, 2014). While the mechanisms of the generation of AT 1 -AA in PE are not clearly understood, studies have shown that the plasma levels of AT 1 -AA are increased in pregnant rats infused with TNF-α, suggesting the involvement of cytokine-induced pathways (LaMarca et al, 2008b).…”

Section: Circulating Bioactive Factors In Preeclampsiamentioning

confidence: 99%

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Mechanisms of Endothelial Dysfunction in Hypertensive Pregnancy and Preeclampsia

Possomato-Vieira

Khalil

2016

Advances in Pharmacology

185

117

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Preeclampsia is a pregnancy-related disorder characterized by hypertension, and could lead to maternal and fetal morbidity and mortality. Although the causative factors and pathophysiological mechanisms are unclear, endothelial dysfunction is a major hallmark of preeclampsia. Clinical tests and experimental research have suggested that generalized endotheliosis in the systemic, renal, cerebral and hepatic circulation could decrease endothelium-derived vasodilators such as nitric oxide, prostacyclin and hyperpolarization factor and increase vasoconstrictors such as endothelin-1 and thromboxane A2, leading to increased vasoconstriction, hypertension and other manifestation of preeclampsia. In search for the upstream mechanisms that could cause endothelial dysfunction, certain genetic, demographic and environmental risk factors have been suggested to cause abnormal expression of uteroplacental integrins, cytokines and matrix metalloproteinases, leading to decreased maternal tolerance, apoptosis of invasive trophoblast cells, inadequate spiral arteries remodeling, reduced uterine perfusion pressure (RUPP), and placental ischemia/hypoxia. RUPP may cause imbalance between the anti-angiogenic factors soluble fms-like tyrosine kinase-1 and soluble endoglin and the pro-angiogenic factors vascular endothelial growth factor and placental growth factor, or stimulate the release of other circulating bioactive factors such as inflammatory cytokines, hypoxia-inducible factor-1, reactive oxygen species, and angiotensin AT1 receptor agonistic autoantibodies. These circulating factors could then target endothelial cells and cause generalized endothelial dysfunction. Therapeutic options are currently limited, but understanding the factors involved in endothelial dysfunction could help design new approaches for prediction and management of preeclampsia.

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“…These autoantibodies cause hypertension and proteinuria when introduced into pregnant or nonpregnant mice and presumably contribute to these features in the women with preeclampsia from whom they were obtained. In addition to preeclampsia, these pathogenic autoantibodies are also associated with hypertensive conditions outside of pregnancy including malignant hypertension, refractory hypertension, and primary aldosteronism . An interesting feature of these autoantibodies is that they uniformly recognize the same epitope (AFHYESQ) located on the second extracellular loop of AT 1 Rs.…”

Section: Introductionmentioning

confidence: 99%

Transglutaminase is a Critical Link Between Inflammation and Hypertension

Luo

Liu

Elliott

et al. 2016

JAHA

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BackgroundThe pathogenesis of essential hypertension is multifactorial with different underlying mechanisms contributing to disease. We have recently shown that TNF superfamily member 14 LIGHT (an acronym for homologous to lymphotoxins, exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for herpes virus entry mediator, a receptor expressed by T lymphocytes, also known as TNFSF14) induces hypertension when injected into mice. Research reported here was undertaken to examine the role of transglutaminase (TGase) in LIGHT‐induced hypertension.Methods and ResultsInitial experiments showed that plasma and kidney TGase activity was induced by LIGHT infusion (13.91±2.92 versus 6.75±1.92 mU/mL and 19.86±3.55 versus 12.00±0.97 mU/10 μg) and was accompanied with hypertension (169±7.16 versus 117.17±11.57 mm Hg at day 14) and renal impairment (proteinuria, 61.33±23.21 versus 20.38±9.01 μg/mg; osmolality, 879.57±93.02 versus 1407.2±308.04 mmol/kg). The increase in renal TGase activity corresponded to an increase in RNA for the tissue TGase isoform, termed TG2. Pharmacologically, we showed that LIGHT‐induced hypertension and renal impairment did not occur in the presence of cystamine, a well‐known competitive inhibitor of TGase activity. Genetically, we showed that LIGHT‐mediated induction of TGase, along with hypertension and renal impairment, was dependent on interleukin‐6 and endothelial hypoxia inducible factor‐1α. We also demonstrated that interleukin‐6, endothelial hypoxia inducible factor‐1α, and TGase are required for LIGHT‐induced production of angiotensin receptor agonistic autoantibodies.ConclusionsThus, LIGHT‐induced hypertension, renal impairment, and production of angiotensin receptor agonistic autoantibodies require TGase, most likely the TG2 isoform. Our findings establish TGase as a critical link between inflammation, hypertension, and autoimmunity.

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Angiotensin II type 1 receptor autoantibody as a novel regulator of aldosterone independent of preeclampsia

Cited by 14 publications

References 35 publications

Matrix Metalloproteinases in Normal Pregnancy and Preeclampsia

Matrix Metalloproteinases in Normal Pregnancy and Preeclampsia

Mechanisms of Endothelial Dysfunction in Hypertensive Pregnancy and Preeclampsia

Transglutaminase is a Critical Link Between Inflammation and Hypertension

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