Elabela Protects Spontaneously Hypertensive Rats From Hypertension and Cardiorenal Dysfunctions Exacerbated by Dietary High-Salt Intake

Abstract

Objectives: Arterial hypertension, when exacerbated by excessive dietary salt intake, worsens the morbidity and mortality rates associated with cardiovascular and renal diseases. Stimulation of the apelinergic system appears to protect against several circulatory system diseases, but it remains unknown if such beneficial effects are conserved in severe hypertension. Therefore, we aimed at determining whether continuous infusion of apelinergic ligands (i.e., Apelin-13 and Elabela) exerted cardiorenal protective effects in spontaneously hypertensive (SHR) rats receiving high-salt diet.Methods: A combination of echocardiography, binding assay, histology, and biochemical approaches were used to investigate the cardiovascular and renal effects of Apelin-13 or Elabela infusion over 6 weeks in SHR fed with normal-salt or high-salt chow.Results: High-salt intake upregulated the cardiac and renal expression of APJ receptor in SHR. Importantly, Elabela was more effective than Apelin-13 in reducing high blood pressure, cardiovascular and renal dysfunctions, fibrosis and hypertrophy in high-salt fed SHR. Unlike Apelin-13, the beneficial effects of Elabela were associated with a counter-regulatory role of the ACE/ACE2/neprilysin axis of the renin-angiotensin-aldosterone system (RAAS) in heart and kidneys of salt-loaded SHR. Interestingly, Elabela also displayed higher affinity for APJ in the presence of high salt concentration and better resistance to RAAS enzymes known to cleave Apelin-13.Conclusion: These findings highlight the protective action of the apelinergic system against salt-induced severe hypertension and cardiorenal failure. As compared with Apelin-13, Elabela displays superior pharmacodynamic and pharmacokinetic properties that warrant further investigation of its therapeutic use in cardiovascular and kidney diseases.

ELABELA protects against diabetic kidney disease by activating high glucose-inhibited renal tubular autophagy

“…ELA, a novel endogenous molecule, is predominantly expressed in the kidney, heart, blood vessels, and other tissues [ 24 ] . It has been identified to play important roles in various organisms and has the potential to alleviate cardiac and renal remodeling [ 25 – 26 , 31 ] . Previous studies showed the possibility that ELA might exert beneficial effects on ischemia-reperfusion renal injury recovery [ 28 ] .…”

APJ as Promising Therapeutic Target of Peptide Analogues in Myocardial Infarction- and Hypertension-Induced Heart Failure

“…Indeed, apelin/ELA and AngII exerted an opposite effect on vessels. In this regard, it has been reported that administration of either apelin or ELA had a blood pressure-lowering effect, potentially indicating a therapeutic role of these peptides in reverting hypertension, thus reducing the risk of developing HF [ 67 , 68 ]. In addition, apelin is capable of boosting ACE2 expression, and this is another mechanism by which it counteracts RAS.…”

“…In line with the in vitro results, apelin KO mice also showed downregulation of ACE2 expression and, consequently, low ACE2 protein level [ 69 , 70 ]. Of note, ACE2, which primarily acts on AngiII, has a role in apelin metabolism because it can cleave apelin into inactive isoforms, though it is unable to degrade ELA [ 23 , 66 , 67 ]. Conversely, ELA did not affect ACE2 expression, but it reduced angiotensin-induced blood pressure via downregulation of ACE expression.…”

Molecular mechanisms of sacubitril/valsartan in cardiac remodeling

“…Additionally, the apelinergic system (composed of apelin and elabela as well as APJ receptors) is believed to be a promising target for the treatment of cardiovascular disease. Both apelin and elabela possess inodilator properties ( Sainsily et al, 2021 ). However, the effects of sacubitril/valsartan on apelin and elabela have not been studied.…”