Pharmacological and immunohistochemical characterization of the APJ receptor and its endogenous ligand apelin

Medhurst, Andrew D.; Jennings, C.A.; Robbins, Melanie J.; Davis, Robert P.; Ellis, Catherine; Winborn, Kim; Lawrie, K. W. M.; Hervieu, Guillaume; Riley, Graham J.; Bolaky, Jane E.; Herrity, Nicole C.; Murdock, Paul R.; Darker, John G.

doi:10.1046/j.1471-4159.2003.01587.x

Cited by 395 publications

(523 citation statements)

References 23 publications

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“…Low apj mRNA expression has previously been shown in human pancreas but it was not detected in rat pancreas (11). A possible species difference could account for this discrepancy, or it could be due to a dilution effect when the expression was studied in whole pancreas, since it is possible that the apj receptor only is expressed in islet cells.…”

Section: Insulin Secretion and Glucose Oxidation In Vitromentioning

confidence: 91%

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The apj receptor is expressed in pancreatic islets and its ligand, apelin, inhibits insulin secretion in mice

Winzell

Magnusson

Åhrén

2005

Regulatory Peptides

177

114

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Apelin is the endogenous ligand of the G-protein coupled apj receptor. Apelin is expressed in the brain, the hypothalamus and the stomach and was recently shown also to be an adipokine secreted from the adipocytes. Although apelin has been suggested to be involved in the regulation of food intake, it is not known whether the peptide affects islet function and glucose homeostasis. We show here that the apj receptor is expressed in pancreatic islets and that intravenous administration of full-length apelin-36 (2 nmol/kg) inhibits the rapid insulin response to intravenous glucose (1g/kg) by 35% in C57BL/6J mice. Thus, the acute (1-5 min) insulin response to intravenous glucose was 682±23 pmol/l after glucose alone (n=17) and 445±58 pmol/l after glucose plus apelin-36 (n=18; P=0.017). This was associated with impaired glucose elimination (the 5-20 min glucose elimination was 2.9±0.1%/min after glucose alone versus 2.3±0.2%/min after glucose plus apelin-36, P=0.008). Apelin (2nmol/kg) also inhibited the insulin response to intravenous glucose in obese insulin resistant high-fat fed C57BL/6J mice (P=0.041). After 60 min incubation of isolated islets from normal mice, insulin secretion in the presence of 16.7 mmol/l glucose was inhibited by apelin-36 at 1 µmol/l, whereas apelin-36 did not significantly affect insulin secretion at 2.8 or 8.3 mmol/l glucose or after stimulation of insulin secretion by KCl. Islet glucose oxidation at 16.7 mmol/l was not affected by apelin-36. We conclude that the apj receptor is expressed in pancreatic islets and that apelin-36 inhibits glucose-stimulated insulin secretion both in vivo and in vitro.This may suggest that the islet beta-cells are targets for apelin-36.

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Section: Insulin Secretion and Glucose Oxidation In Vitromentioning

confidence: 91%

“…The endogenous ligand for the apj receptor is apelin, which was initially demonstrated in stomach extracts in 1998 (8). Later studies have shown that apelin mRNA is expressed in several tissues, as for example in several regions in the CNS, in the heart, lung, placenta, mammary gland and gastrointestinal tract (3,5,(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

The apj receptor is expressed in pancreatic islets and its ligand, apelin, inhibits insulin secretion in mice

Winzell

Magnusson

Åhrén

2005

Regulatory Peptides

177

114

View full text Add to dashboard Cite

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“…Overall, apelin and APJ mRNA transcripts and respective peptides, are abundantly present in central nervous system and also in peripheral tissues such as vascular endothelium, heart, lung, kidney and mammary gland [18,25,40,32,10,21], suggesting a functional role of apelin/APJ in these tissues. Remarkably the bulk of the studies report cardiovascular actions of apelin/APJ.…”

Section: Introductionmentioning

confidence: 99%

The apelinergic system in the developing lung: Expression and signaling

et al. 2011

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a b s t r a c tApelin and its receptor APJ constitute a signaling pathway best recognized as an important regulator of cardiovascular homeostasis. This multifunctional peptidergic system is currently being described to be involved in embryonic events which extend into vascular, ocular and heart development. Additionally, it is highly expressed in pulmonary tissue. Therefore, the aim of this study was to investigate the role of apelinergic system during fetal lung development. Immunohistochemistry and Western blot analysis were used to characterize apelin and APJ expression levels and cellular localization in normal fetal rat lungs, at five different gestational ages as well as in the adult. Fetal rat lung explants were cultured in vitro with increasing doses of apelin. Treated lung explants were morphometrically analyzed and assessed for MAPK signaling modifications. Both components of the apelinergic system are constitutively expressed in the developing lung, with APJ exhibiting monomeric, dimeric and oligomeric forms in the pulmonary tissue. Pulmonary epithelium also displayed constitutive nuclear localization of the receptor. Fetal apelin expression is higher than adult expression. Apelin supplementation inhibitory effect on branching morphogenesis was associated with a dose dependent decrease in p38 and JNK phosphorylation. The results presented provide the first evidence of the presence of an apelinergic system operating in the developing lung. Our findings also suggest that apelin inhibits fetal lung growth by suppressing p38 and JNK signaling pathways.

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“…Recently, the endogenous ligand of APJ was identified from bovine stomach, and this peptide was named apelin (for APJ endogenous ligand) (2). APJ and apelin are expressed in several tissues including the cardiovascular and the central nervous systems (3)(4)(5)(6), and the structure of APJ and apelin is highly conserved among species, suggesting its important physiological roles.…”

mentioning

confidence: 99%

Regulatory Roles for APJ, a Seven-transmembrane Receptor Related to Angiotensin-type 1 Receptor in Blood Pressure in Vivo

Ishida

Hashimoto

et al. 2004

Journal of Biological Chemistry

366

294

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APJ is a G-protein-coupled receptor with seven transmembrane domains, and its endogenous ligand, apelin, was identified recently. They are highly expressed in the cardiovascular system, suggesting that APJ is important in the regulation of blood pressure. To investigate the physiological functions of APJ, we have generated mice lacking the gene encoding APJ. The base-line blood pressure of APJ-deficient mice is equivalent to that of wild-type mice in the steady state. The administration of apelin transiently decreased the blood pressure of wild-type mice and a hypertensive model animal, a spontaneously hypertensive rat. On the other hand, this hypotensive response to apelin was abolished in APJ-deficient mice. This apelininduced response was inhibited by pretreatment with a nitric-oxide synthase inhibitor, and apelin-induced phosphorylation of endothelial nitric-oxide synthase in lung endothelial cells from APJ-deficient mice disappeared. In addition, APJ-deficient mice showed an increased vasopressor response to the most potent vasoconstrictor angiotensin II, and the base-line blood pressure of double mutant mice homozygous for both APJ and angiotensin-type 1a receptor was significantly elevated compared with that of angiotensintype 1a receptor-deficient mice. These results demonstrate that APJ exerts the hypotensive effect in vivo and plays a counterregulatory role against the pressor action of angiotensin II.A family of G protein-coupled receptors bind a large variety of ligands and plays an essential role for physiological functions in vivo including the maintenance of homeostasis in the cardiovascular system. APJ (a putative receptor protein related to the angiotensin-type 1 receptor (AT1)) 1 is a G protein-coupled receptor that was isolated from human genomic DNA using the polymerase chain reaction (1). The APJ has a 31% amino acid sequence homology with the AT1, but APJ does not display specific binding for angiotensin II, which is the ligand of AT1 and exerts a pressor action in the blood pressure regulation (1). Recently, the endogenous ligand of APJ was identified from bovine stomach, and this peptide was named apelin (for APJ endogenous ligand) (2). APJ and apelin are expressed in several tissues including the cardiovascular and the central nervous systems (3-6), and the structure of APJ and apelin is highly conserved among species, suggesting its important physiological roles.Intravenous administration of apelin suggested a hypotensive effect in rat (5, 7-9). On the other hand, apelin potently contracts human saphenous vein smooth muscle cells in vitro (10), indicating that apelin is a potent vasoconstrictor. Thus, at this moment, the action of apelin in blood pressure regulation is controversial, and it is still unclear whether these actions of apelin are really through APJ because of the absence of specific receptor blocker to clarify the in vivo functions of APJ. Therefore, in this study, by using animal models such as APJ-deficient mice, APJ/AT1a double knock-out mice, and spontaneously hypertens...

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Pharmacological and immunohistochemical characterization of the APJ receptor and its endogenous ligand apelin

Cited by 395 publications

References 23 publications

The apj receptor is expressed in pancreatic islets and its ligand, apelin, inhibits insulin secretion in mice

The apj receptor is expressed in pancreatic islets and its ligand, apelin, inhibits insulin secretion in mice

The apelinergic system in the developing lung: Expression and signaling

Regulatory Roles for APJ, a Seven-transmembrane Receptor Related to Angiotensin-type 1 Receptor in Blood Pressure in Vivo

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