A metabolically stable apelin-17 analog decreases AVP-induced antidiuresis and improves hyponatremia

Adrien Flahault, Pierre-Emmanuel Girault-Sotias, Mathilde Keck, Rodrigo Alvear-Perez, Nadia Mota, Lucie Estéoulle, Sridévi M. Ramanoudjame, Xavier Iturrioz, Dominique Bonnet () and Catherine Llorens-Cortes ()
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Adrien Flahault: Collège de France
Pierre-Emmanuel Girault-Sotias: Collège de France
Mathilde Keck: Collège de France
Rodrigo Alvear-Perez: Collège de France
Nadia Mota: Collège de France
Lucie Estéoulle: University of Strasbourg
Sridévi M. Ramanoudjame: University of Strasbourg
Xavier Iturrioz: Collège de France
Dominique Bonnet: University of Strasbourg
Catherine Llorens-Cortes: Collège de France

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract Apelin and arginine-vasopressin (AVP) are conversely regulated by osmotic stimuli. We therefore hypothesized that activating the apelin receptor (apelin-R) with LIT01-196, a metabolically stable apelin-17 analog, may be beneficial for treating the Syndrome of Inappropriate Antidiuresis, in which AVP hypersecretion leads to hyponatremia. We show that LIT01-196, which behaves as a potent full agonist for the apelin-R, has an in vivo half-life of 156 minutes in the bloodstream after subcutaneous administration in control rats. In collecting ducts, LIT01-196 decreases dDAVP-induced cAMP production and apical cell surface expression of phosphorylated aquaporin 2 via AVP type 2 receptors, leading to an increase in aqueous diuresis. In a rat experimental model of AVP-induced hyponatremia, LIT01-196 subcutaneously administered blocks the antidiuretic effect of AVP and the AVP-induced increase in urinary osmolality and induces a progressive improvement of hyponatremia. Our data suggest that apelin-R activation constitutes an original approach for hyponatremia treatment.

Date: 2021
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DOI: 10.1038/s41467-020-20560-y

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