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Reciprocal Regulation of Plasma Apelin and Vasopressin by Osmotic Stimuli

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Reciprocal Regulation of Plasma Apelin and Vasopressin by Osmotic Stimuli CLINICAL RESEARCH www.jasn.org Reciprocal Regulation of Plasma Apelin and Vasopressin by Osmotic Stimuli Michel Azizi,* Xavier Iturrioz,† Anne Blanchard,* Se´verine Peyrard,* Nadia De Mota,† Nicolas Chartrel,‡ Hubert Vaudry,‡ Pierre Corvol,§ and Catherine Llorens-Cortes† *Assistance Publique Hoˆpitaux de Paris, Hoˆpital Europe´en Georges Pompidou, Universite´ Paris Descartes, Faculte´ de Me´decine, and INSERM, CIC 9201, †INSERM, Unit 691, Colle`ge de France, ‡INSERM, Unit 413, Universite´de Rouen, and §INSERM, Unit 36, Colle`ge de France, Paris, France ABSTRACT Apelin is a neuropeptide that co-localizes with vasopressin (AVP) in magnocellular neurons and is involved in body fluid homeostasis. Osmotic stimuli have opposite effects on the regulation of apelin and AVP secretion in animal models, but whether this is true in humans is unknown. This study investigated the relationship among osmolality, apelin, and AVP in 10 healthy men after infusion of hypertonic saline or loading with water to increase and decrease plasma osmolality, respectively. Increasing plasma osmolality was accompanied by a parallel, linear increase in plasma AVP concentration and by a decrease in plasma apelin concentration. In contrast, decreasing plasma osmolality by water loading reduced plasma AVP concentration and rapidly increased plasma apelin concentration. These findings suggest that regulation of apelin secretion contributes to the maintenance of body fluid homeostasis. J Am Soc Nephrol 19: 1015–1024, 2008. doi: 10.1681/ASN.2007070816 The osmotic pressure of body fluids is maintained (putative receptor protein related to the angioten- within a remarkably narrow range in healthy adults. sin receptor AT1).6,7 It is a 36–amino acid peptide Body fluid homeostasis depends on neuronal path- (apelin 36) derived from a single 77–amino acid ways bearing very sensitive osmoreceptors,1 located precursor, proapelin.6,8,9 Proapelin has a fully con- along the lamina terminalis, including the circum- served C-terminal 17–amino acid sequence, apelin ventricular organs, such as the subfornical organ 17 (K17F), including the pyroglutamyl form of ape- and the organum vasculosum of the lamina termi- lin 13 (pE13F). K17F and pE13F both are present in nalis as well as the median preoptic nucleus.2 The rat brain and plasma,10 and apelin 36 is present in subfornical organ and organum vasculosum of the testis and uterus.11 All peptides exhibit a high affin- lamina terminalis are neuronally interconnected ity for the human8,12,13 and the rat apelin recep- with each other as well as with the median preoptic tors.14 Apelin possesses various cardiovascular nucleus and the hypothalamic paraventricular and functions (for reviews,15–17). Apelin and its receptor supraoptic nuclei.3 These neuronal pathways con- have been detected in the endothelial cells of large vert small changes in osmolality into a neuronal sig- conduit arteries, coronary vessels, and the endocar- nal to neurons that influence sensations of thirst 2 and systemic arginine vasopressin (AVP) release, Received July 25, 2007. Accepted November 13, 2007 thereby adjusting the intake or output of water to 4,5 Published online ahead of print. Publication date available at counteract changes in solute concentration. www.jasn.org. A recently discovered peptide, apelin, may also Correspondence: Dr. Catherine Llorens-Cortes, INSERM, Unit play a major role in the maintenance of body fluid 691, Colle`ge de France, Paris, F-75005 France. Phone: 33-1-44- homeostasis. Apelin, initially isolated from bovine 27-16-63; Fax: 33-1-44-27-16-67; E-mail: c.llorens-cortes@ stomach extracts,6 is the endogenous ligand of the college-de-france.fr human orphan G protein–coupled receptor APJ Copyright ᮊ 2008 by the American Society of Nephrology J Am Soc Nephrol 19: 1015–1024, 2008 ISSN : 1046-6673/1905-1015 1015 CLINICAL RESEARCH www.jasn.org dium of the right atrium.18–20 Apelin injection decreases BP in animals,9,21–23 via nitric oxide production.21 Apelin has a pos- itive inotropic effect both on isolated perfused rat hearts ex vivo24 and on normal and postmyocardial infarction rat hearts in vivo.25 Apelin administration in mice reduces left ventricular preload and afterload and increases contractile reserve and car- diac output.26 Finally, apelin-deficient mice develop heart fail- ure with aging.27 Apelin and its receptor both are widely distributed in the brain9,14,28,29 but are particularly abundant in the supraoptic nucleus and paraventricular nucleus, where they co-localize with AVP in magnocellular neurons.10,29–31 Intracerebro- ventricular injection of K17F inhibits the typical phasic fir- ing pattern of AVP neurons in lactating rats, resulting in decreased systemic AVP release and increased aqueous Figure 1. Reverse-phase HPLC analysis of apelin-IR in human diuresis.10 Moreover, water deprivation in rats while in- plasma. A human plasma sample was chromatographed on a creasing systemic AVP release and causing depletion of Vydac C4 column, and the immunoreactive material contained in hypothalamic AVP stores decreases plasma apelin concen- the HPLC fractions was quantified by RIA. This chromatogram is trations and results in hypothalamic accumulation of the representative of four independent experiments giving the fol- lowing percentage of each apelin fragment: pE13F, 30 Ϯ 13%, peptide. Thus, the two peptides are conversely regulated K17F, 56 Ϯ 12%, and apelin 36, 14 Ϯ 7%. The dotted line to optimize AVP release into the blood circulation and indicates the acetonitrile gradient. The arrows indicate the elution 10 prevent additional water loss through the kidney. positions of the reference peptides. Whether such opposite regulation of apelin and AVP secre- tion in response to osmotic stimuli is found in humans re- mains unknown. and 8:00 p.m. with no significant changes associated with the The aim of this clinical investigation was to examine the 12-h overnight fluid and food restriction (Table 1). The me- relationship between plasma osmolality, plasma apelin, and dian (IQR) within-subject variability in plasma apelin concen- plasma AVP in healthy adults in various states of hydration. tration as assessed by testing plasma samples collected between Hydration was modified by administration of a hypertonic sa- 8:00 a.m. on day Ϫ1 to 9:00 a.m. on day 1 was 18.6% (13.3 to line infusion and by water loading to increase and decrease 23.6%) and that of plasma AVP concentration was 23.3% (18.2 plasma osmolality, respectively. to 36.8%). There was no significant difference in plasma apelin or in plasma AVP concentrations between the individuals assigned to the hypertonic saline infusion on day 1 (group 1) and those RESULTS assigned to the water loading test on day 1 (group 2) at any time point between 8:00 a.m. on day Ϫ1 and 9:00 a.m. on day 1 Characterization of the Molecular Forms of Apelin (Table 1). The plasma apelin/AVP ratio was also similar be- Present in Human Plasma tween the two groups (Table 1). There was no significant cor- Apelin immunoreactivity (apelin-IR) was resolved as two ma- relation between plasma apelin concentration and plasma AVP jor components eluting in fraction 28 and fractions 31 to 32 concentration in the absence of osmotic challenge (data not and a minor component eluting in fraction 40 (Figure 1). Cal- shown). Although plasma osmolality levels significantly dif- ibration of the C4 column with apelin fragments revealed that fered between the two groups (Table 1), probably because the prominent immunoreactive compounds co-eluted with group 1 and group 2 were studied sequentially at different pE13F and K17F, respectively, and that the apelin-IR present in times of the year (see the Concise Methods section), there was fraction 40 exhibited the same retention time as synthetic ape- no significant correlation between plasma apelin or plasma lin 36 (Figure 1). AVP concentrations and plasma osmolality in the absence of osmotic challenge (data not shown). Plasma Apelin Levels in Physiologic Unrestricted Water Intake Conditions on Day ؊1 Hypertonic Saline Infusion in Group 1 At 8:00 a.m. on day Ϫ1, the plasma apelin concentration in 10 The hypertonic saline infusion induced a smooth and linear Ϯ Ϯ healthy individuals was 477 167 fmol/ml; plasma osmolality increase in plasma osmolality from 288 1.6 mOsm/kg H2O Ϯ Ϯ (286 4 mOsm/kg H2O) and plasma AVP concentration (me- at baseline to 302 3.1 mOsm/kg H2O at the end of the infu- dian [interquartile range (IQR)] 1.8 [1.4 to 3.0] fmol/ml) both sion (P Ͻ 0.0001 versus baseline; Figure 2A) and in plasma were within the physiologic range. Plasma osmolality, apelin, sodium (Naϩ) concentration (P Ͻ 0.0001 versus baseline; Ta- AVP, and apelin/AVP ratio remained stable between 8:00 a.m. ble 2), associated with a parallel linear increase in plasma AVP 1016 Journal of the American Society of Nephrology J Am Soc Nephrol 19: 1015–1024, 2008 J Am Soc Nephrol Table 1. Plasma apelin, osmolality, and AVP levels in physiologic unrestricted water intake conditions from day Ϫ1 (8:00 a.m.) to day 1 (9:00 a.m.) in 10 healthy male participantsa Time Parameter 8:00 a.m. 12:00 p.m. 4:00 p.m. 8:00 p.m. 12:00 a.m. 9:00 a.m. Plasma apelin (fmol/ml; mean Ϯ SD) 19: all participants (n ϭ 10) 478 Ϯ 167 467 Ϯ 133 414 Ϯ 90 472 Ϯ 129 433 Ϯ 99 451 Ϯ 158 1015–1024, 2008 group 1 (n ϭ 5) 552 Ϯ 196 541 Ϯ 134 444 Ϯ 46 528 Ϯ 127 503 Ϯ 70 567 Ϯ 124 group 2 (n ϭ 5) 403 Ϯ 101 393 Ϯ 88 384 Ϯ 118 415 Ϯ 117 363 Ϯ 69 335 Ϯ 83 Plasma AVP (fmol/ml; median ͓IQR͔) all participants (n ϭ 10) 1.8 (1.4 to 3.0) 2.3 (1.9 to
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