Role of the Vasopressin/Apelin Balance and Potential Use of Metabolically Stable Apelin Analogs in Water Metabolism Disorders

Abstract

Apelin, a (neuro)vasoactive peptide, plays a prominent role in controlling body fluid homeostasis and cardiovascular functions. In animal models, experimental data demonstrate that intracerebroventricular injection of apelin into lactating rats inhibits the phasic electrical activity of arginine vasopressin (AVP) neurons, reduces plasma AVP levels, and increases aqueous diuresis. In the kidney, apelin increases diuresis by increasing the renal microcirculation and by counteracting the antidiuretic effect of AVP at the tubular level. Moreover, after water deprivation or salt loading, in humans and in rodents, AVP and apelin are conversely regulated to facilitate systemic AVP release and to avoid additional water loss from the kidney. Furthermore, apelin and vasopressin secretion are significantly altered in various water metabolism disorders including hyponatremia and polyuria-polydipsia syndrome. Since the in vivo half-life of apelin is in the minute range, metabolically stable apelin analogs were developed. The efficacy of these lead compounds for decreasing AVP release and increasing both renal blood flow and diuresis, make them promising candidates for the treatment of water retention and/or hyponatremic disorders.

International Union of Basic and Clinical Pharmacology. CVII. Structure and Pharmacology of the Apelin Receptor with a Recommendation that Elabela/Toddler Is a Second Endogenous Peptide Ligand

“…The following should be consulted for more details of the role of apelin receptor ligands in homeostasis, cell signaling, and aging: Galanth et al (2012), O’Carroll et al (2013), Chapman et al (2014), Flahault et al (2017), Zhou et al (2017). The following reviews focus on the apelin signaling pathway in disease: cardiovascular, Scimia et al (2014), Dalzell et al (2015), Kuba et al (2019); myocardial ischemia and reperfusion injury, Chen et al (2016); vascular smooth muscle, Luo et al (2018); endothelial cell dysfunction, Cheng et al (2019); pulmonary hypertension, Kim (2014); hypertension, Gilbert (2017); stroke Wu et al (2017b); renal, Huang et al (2018); liver, Lv et al (2017); cancer, Yang et al (2016); diabetes and metabolic diseases Castan-Laurell et al (2012, 2019), Bertrand et al (2015), Chaves-Almagro et al, (2015), Hu et al, (2016), Alipour et al, (2017).…”

Elabela/Toddler and apelin bind differently to the apelin receptor

“…Finally, Elabela/Toddler has been shown, to decrease arterial blood pressure (BP), to improve left ventricular contractility and to increase diuresis more potently than pE13F in rats in vivo 11,15 . Thus, Elabela/Toddler appears to be an interesting peptide with potential therapeutic properties against cardiovascular diseases and water‐balance disorders such as hyponatremia 18 …”

The apelinergic system: a perspective on challenges and opportunities in cardiovascular and metabolic disorders

“…In contrast with these studies demonstrating the aquaretic role of apelin in rodents, water‐deprived Aplnr −/− mice were unable to concentrate their urine to the same extent as wild‐type mice . A possible explanation for this discrepancy is that in whole‐body KO mouse model, the total absence of apelin receptor during fetal and adult life elicits compensatory mechanisms, leading to opposite effects on urine output observed following exogenous apelin administration.…”