The search for a G protein coupled receptors (GPCR) specific for angiotensin III led us to isolate the murine homolog of the human orphan receptor, APJ, that shares 31% sequence identity with the angiotensin II receptor type 1 (AT1). At the end of 1998, the sequence of the endogenous ligand of the human APJ receptor was isolated and named apelin. We pharmacologically characterized this receptor. We then demonstrated that apelin and its receptor are co-expressed with arginine vasopressin (AVP) in magnocellular vasopressinergic neurons from the supraoptic and paraventricular hypothalamic nuclei. We showed that the central injection of apelin in lactating rats decreased the phasic electrical activity of AVP neurons and the secretion of AVP into the bloodstream, increasing aqueous diuresis. Apelin has also a diuretic effect via a direct renal action by increasing renal blood flow and by counteracting in collecting ducts, the antidiuretic effect of AVP occurring via vasoppressin receptors type 2 (V2).

Apelin is thus a natural inhibitor of the anti-diuretic effects of AVP. Finally, in rats and humans, we found that apelin and AVP are conversely regulated by osmotic stimuli, thereby both participating to the maintenance of body fluid homeostasis. Apelin and its receptor are also present in the heart, kidney and blood vessels and the systemic injection of apelin decreases blood pressure, improves cardiac contractility and reduces cardiac loading. Apelin may therefore play a crucial role in maintaining water and electrolyte balance and cardiovascular function.

Since the half-life of apelin in the blood circulation is in the minute range, we therefore aimed to develop metabolically stable apelin-17 analogs. We generated P92 by classic chemical substitutions and LIT01-196 by original addition of a fluorocarbon chain to the N terminus of K17F. Both analogs were much more stable in plasma (half-life >24 h for LIT01-196) than K17F (4.6min). Analogs displayed a subnanomolar affinity for the apelin receptor and behaved as full agonists with regard to cAMP production, ERK phosphorylation, and apelin receptor internalization. Ex vivo, these compounds induced vasorelaxation of rat aorta and glomerular arterioles, respectively, precontracted with norepinephrine and angiotensin II, and increased cardiac contractility. In vivo, after intracerebroventricular administration in water-deprived mice, P92 and LIT01-196 were 6 and 160 times, respectively, more efficient at inhibiting systemic vasopressin release than K17F. Administered intravenously (nmol/kg range) in normotensive rats, these analogs potently increased urine output and induced a profound and sustained decrease in arterial blood pressure. In conclusion, these new compounds, which favor diuresis and improve cardiac contractility while reducing vascular resistances, represent promising candidates for the treatment of heart failure and water retention/ hyponatremic disorders.

 

Catherine LLORENS-CORTES

Directrice du laboratoire "Neuropeptides centraux et régulations hydrique et cardiovasculaire"

Inserm U1050, CIRB, Collège de France, Paris

Invited by Xavier Houard.

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Centre De Rercherche (CdR) Saint-Antoine
INSERM - UMR S 938

Hôpital St-Antoine

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Saint-Antoine Research Center

The CRSA was renewed jointly by Inserm and UPMC as UMRS_938, for 5 years from January 2014 to December 2018.

Last publications

Presentation of the Centre

The CRSA regroups a very strong potential for biomedical research oriented towards both fundamental and translational research. Research is performed in association with the clinical and biological departments of the Saint-Antoine-Tenon-Armand Trousseau hospitals belonging to the same General Hospital Group. The CRSA is composed of 14 accredited research teams and one administrative team located mainly on the site of the Saint-Antoine hospital but also of hospital Armand Trousseau.

Scientific activities

Two scientific interacting orientations are identified: Research in Oncology and Haematology; and Research in Metabolism and Inflammation and Tissue Repair. They include several aspects of translational research : Fundamental; Preclinical; Pathophysiological and Aspects more specifically clinical.

Collective facilities and technological platforms

The Research Centre developed collective facilities (such as L2, L3 laboratories) but is also implicated in UPMC networks (for technologies such as Mass spectrometry, lipidomic and proteomic; Cell and tissue imagery and flow cytometry ; Imagery and functional exploration of small animals)