Angiotensin type 2 receptors: blood pressure regulation and end organ damage

Sumners, Colin; Kloet, Annette D. de; Krause, Eric G.; Unger, Thomas; Steckelings, Ulrike Muscha

doi:10.1016/j.coph.2015.01.004

Cited by 72 publications

(59 citation statements)

References 51 publications

(62 reference statements)

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“…Moreover, losartan enhanced apelin release above the baseline levels. Since the actions of the AT 2 receptor (AT 2 R) could be unmasked following the AT 1 R blockade (8,46), it is possible that AT 2 R contributes to apelin release from chorionic villi. AT 1 R is the predominant angiotensin receptor in normal and preeclamptic placental chorionic villi (4).…”

Section: Discussionmentioning

confidence: 99%

Downregulation of apelin in the human placental chorionic villi from preeclamptic pregnancies

Yamaleyeva

Chappell

Brosnihan

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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The role of the endogenous apelin system in pregnancy is not well understood. Apelin's actions in pregnancy are further complicated by the expression of multiple forms of the peptide. Using radioimmunoassay (RIA) alone, we established the expression of apelin content in the chorionic villi of preeclamptic (PRE) and normal pregnant women (NORM) at 36 -38 wk of gestation. Total apelin content was lower in PRE compared with NORM chorionic villi (49.7 Ϯ 3.4 vs. 72.3 Ϯ 9.8 fmol/mg protein; n ϭ 20 -22) and was associated with a trend for lower preproapelin mRNA in the PRE. Further characterization of apelin isoforms by HPLC-RIA was conducted in pooled samples from each group. The expression patterns of apelin peptides in NORM and PRE villi revealed little or no apelin-36 or apelin-17. Pyroglutamate apelin-13 [(Pyr 1 )-apelin-13] was the predominant form of the peptide in NORM and PRE villi. Angiotensin-converting enzyme 2 (ACE2) activity was higher in PRE villi (572.0 Ϯ 23.0 vs. 485.3 Ϯ 24.8 pmol·mg Ϫ1 ·min Ϫ1 ; n ϭ 18 -22). A low dose of ANG II (1 nM; 2 h) decreased apelin release in NORM villous explants that was blocked by the ANG II receptor 1 (AT1) antagonist losartan. Moreover, losartan enhanced apelin release above the 2-h baseline levels in both NORM and PRE villi (P Ͻ 0.05). In summary, these studies are the first to demonstrate the lower apelin content in human placental chorionic villi of PRE subjects using quantitative RIA. (Pyr 1 )-apelin-13 is the predominant form of endogenous apelin in the chorionic villi of NORM and PRE. The potential mechanism of lower apelin expression in the PRE villi may involve a negative regulation of apelin by ANG II. apelin-13; apelin receptor; ACE2; pregnancy; explant PREECLAMPSIA IS A pregnancy-induced hypertensive disorder that occurs in 5-7% of all pregnancies worldwide (54). It is associated with maternal perinatal morbidity and mortality and a high risk of premature birth and fetal growth restriction. Despite continued research, the pathogenesis of preeclampsia is still unknown. The endogenous apelin system is an emerging target for the regulation of cardiovascular homeostasis (22); however, its role in pregnancy is not well understood. The levels of preproapelin mRNA are widespread in human tissues, and high levels were identified in the placenta (38), suggesting a possible placental origin of apelin in pregnancy. Apelin may have a paracrine role in human chorionic villi as it has been identified in cytotrophoblasts, in syncytiotrophoblasts, and in fetal endothelial cells (13,15). A positive correlation between maternal and fetal plasma apelin was observed in full-term normal pregnancies (37). Moreover, a transplacental transfer of apelin with potential impact on fetal growth was suggested (37). Apelin is a ligand for the human G protein-coupled receptor APJ (40). The role of APJ in embryonic development was shown by the existence of cardiovascular developmental defects in APJ-deficient mice (11). In addition, a small litter size and a significant loss of homozygous ani...

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Section: Discussionmentioning

confidence: 99%

Downregulation of apelin in the human placental chorionic villi from preeclamptic pregnancies

Yamaleyeva

Chappell

Brosnihan

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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“…Whether AT 2 R agonists are antihypertensive by directly reducing peripheral vascular resistance, independently at least in part of their effects on renal Na + excretion, has been controversial (29,30). Clear results have been hindered by lack of highly selective AT 2 R agonists for study.…”

Section: At2r Agonist - Induced Natriuresis and Bp Reductionmentioning

confidence: 99%

Update on angiotensin AT2 receptors

Carey

2016

Current Opinion in Nephrology and Hypertension

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Purpose of the review To update major new findings and concepts introduced during the past year on the role of angiotensin II (Ang II) subtype 2 receptors (AT2Rs) in the control of blood pressure (BP) and renal function. Recent findings AT2R activation prevents sodium (Na+) retention and lowers BP in the Ang II infusion model of experimental hypertension and prevents salt-sensitive hypertension in the obese Zucker rat model of obesity and the metabolic syndrome. Ang II metabolite, des-aspartyl1-Ang II (Ang III) is the predominant AT2R agonist in the kidney and possibly also in the vasculature; a novel synthetic Ang III peptide, β-Pro-Ang III, is vasodepressor and lowers BP in conscious spontaneously hypertensive rats (SHR) in the presence of low-level Ang II type 1 receptor (AT1R) blockade. Because nitric oxide (NO) is a product of AT2R activation, a potential feed forward loop, wherein NO increases AT2R transcription, may reinforce AT2R beneficial actions long term. AT2R activation also reduces proteinuria and oxidative stress in glomerulosclerotic kidneys of high salt obese Zucker rats. Summary Studies during the past year have helped clarify the physiological and pathophysiological roles of AT2Rs and have enhanced the promise of AT2R agonists in cardiovascular and renal disease.

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“…Although the physiological/pathophysiological roles of the AT2 receptor have not been fully elucidated, there is an increasing interest in AT2 receptor functions in the cardiovascular system (8–10). AT2 receptor stimulation causes vasorelaxation through protein kinase A (PKA)-dependent endothelial nitric oxide (NO) synthase (eNOS) activation or paracrine signaling induced by bradykinin/NO/cyclic GMP production (1, 8).…”

Section: Introductionmentioning

confidence: 99%

AT1 receptor signaling pathways in the cardiovascular system

Kawai

Forrester

O’Brien

et al. 2017

Pharmacological Research

182

126

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The importance of the renin angiotensin aldosterone system in cardiovascular physiology and pathophysiology has been well described whereas the detailed molecular mechanisms remain elusive. The angiotensin II type 1 receptor (AT1 receptor) is one of the key players in the renin angiotensin aldosterone system. The AT1 receptor promotes various intracellular signaling pathways resulting in hypertension, endothelial dysfunction, vascular remodeling and end organ damage. Accumulating evidence shows the complex picture of AT1 receptor-mediated signaling; AT1 receptor-mediated heterotrimeric G protein-dependent signaling, transactivation of growth factor receptors, NADPH oxidase and ROS signaling, G protein-independent signaling, including the β-arrestin signals and interaction with several AT1 receptor interacting proteins. In addition, there is functional cross-talk between the AT1 receptor signaling pathway and other signaling pathways. In this review, we will summarize an up to date overview of essential AT1 receptor signaling events and their functional significances in the cardiovascular system.

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Angiotensin type 2 receptors: blood pressure regulation and end organ damage

Cited by 72 publications

References 51 publications

Downregulation of apelin in the human placental chorionic villi from preeclamptic pregnancies

Downregulation of apelin in the human placental chorionic villi from preeclamptic pregnancies

Update on angiotensin AT2 receptors

AT1 receptor signaling pathways in the cardiovascular system

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