Laboratory of Central Neuropeptides in the Regulation of Body Fluid Homeostasis and Cardiovascular Functions, Center for Interdisciplinary Research in Biology, INSERM, Unit U1050, Centre National de la Recherche Scientifique, Unite Mixte de Recherche 7241, Collège de France, Paris, France.
Laboratory of Therapeutic Innovation, Unité Mixte de Recherche 7200, Centre National de la Recherche Scientifique, Faculty of Pharmacy, University of Strasbourg, Illkirch, France.
Nat Commun. 2021 Jan 12;12(1):305. doi: 10.1038/s41467-020-20560-y.
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.
Apelin 和精氨酸加压素（AVP）受渗透刺激的调节相反。因此，我们假设用 LIT01-196（一种代谢稳定的 Apelin-17 类似物）激活 Apelin 受体（apelin-R）可能有益于治疗抗利尿激素分泌不当综合征，其中 AVP 分泌过多导致低钠血症。我们表明，LIT01-196 作为 Apelin-R 的有效完全激动剂，在对照大鼠皮下给药后在血液中的体内半衰期为 156 分钟。在集合管中，LIT01-196 通过 AVP 型 2 受体减少 dDAVP 诱导的 cAMP 产生和磷酸化水通道蛋白 2 的顶端细胞表面表达，导致水利尿增加。在 AVP 诱导的低钠血症大鼠实验模型中，皮下给予 LIT01-196 可阻断 AVP 的抗利尿作用和 AVP 诱导的尿渗透压增加，并逐渐改善低钠血症。我们的数据表明，Apelin-R 激活构成了治疗低钠血症的一种新方法。
