The therapeutic potential of apelin in kidney disease

Abstract

Chronic kidney disease (CKD) is a leading cause of global morbidity and mortality and is independently associated with cardiovascular disease. The mainstay of treatment for CKD is blockade of the renin-angiotensin-aldosterone system (RAAS), which reduces blood pressure and proteinuria and slows kidney function decline. Despite this treatment, many patients progress to kidney failure, which requires dialysis or kidney transplantation, and/or die as a result of cardiovascular disease. The apelin system is an endogenous physiological regulator that is emerging as a potential therapeutic target for many diseases. This system comprises the apelin receptor and its two families of endogenous ligands, apelin and elabela/toddler. Preclinical and clinical studies show that apelin receptor ligands are endothelium-dependent vasodilators and potent inotropes, and the apelin system has a reciprocal relationship with the RAAS. In preclinical studies, apelin regulates glomerular haemodynamics and acts on the tubule to promote aquaresis. In addition, apelin is protective in several kidney injury models. Although the apelin system has not yet been studied in patients with CKD, the available data suggest that apelin is a promising potential therapeutic target for kidney disease.

Fig. 1. The peptide sequences of apelin and ELA isoforms.

a | The amino acid sequences of apelin-36, apelin-17, apelin-13 and [Pyr¹]apelin-13 aligned by the C terminus, which is crucial for receptor binding and biological activity. The N-terminal Gln residue of apelin-13 undergoes translational modification to pyroglutamate, which increases resistance to metabolism by aminopeptidases. The resulting pyroglutamated form of apelin-13, [Pyr¹]apelin-13, is the most abundant apelin isoform in humans^,. b | The predicted amino acid sequences of ELA-32, ELA-21 and ELA-11 isoforms^,. The N-terminal Gln of ELA-32 is predicted to undergo transformation to pyroglutamate. ELA-32 and ELA-21 form bridges between Cys residues. The occurrence and relative abundance of ELA isoforms have not yet been confirmed experimentally. Apelin and ELA isoforms have similar physicochemical properties, particularly within the C terminus.

Fig. 2. Apelin receptor activation leads to a broad range of physiological actions that are mediated by several signalling pathways.

In vascular endothelial cells, binding of apelin or elabela/toddler (ELA) to the apelin receptor results in Gα_i-mediated inhibition of cAMP production and activation of phosphoinositide 3-kinase (PI3K)–AKT signalling cascades, leading to vasodilatation. In cardiomyocytes, activation of the apelin receptor leads to a Gα_q-mediated increase in cardiac contractility and cardiac output through activation of the phospholipase C (PLC)–protein kinase C (PKC) pathway with subsequent enhanced activity of the Na⁺/H⁺ exchanger (NHE) and increased intracellular pH. The increase in intracellular Na⁺ activates the Na⁺/Ca²⁺ exchanger (NCX), leading to a rise in intracellular calcium and increased myocardial contractility. Apelin-13 is thought to promote cardiomyocyte hypertrophy via PI3K–AKT–ERK1/ERK2–p70S6K and PI3K-induced autophagy (not shown). The metabolic effects of apelin receptor activation have been proposed to be mediated via Gα_i and Gα_q. Signalling via β-arrestin leads to apelin receptor desensitization and internalization. The internalized receptor is targeted for degradation or recycled to the cell surface. β-Arrestin-mediated signalling may also contribute to the actions of apelin. DAG, diacylglycerol; eNOS, endothelial nitric oxide synthase; ERK1, extracellular signal-regulated kinase 1; GRKβ: G protein coupled receptor kinase-β; IP3, inositol tris-phosphate; MEK1, mitogen-activated protein kinase 1; NO, nitric oxide; pAKT, phosphorylated AKT; PIP₂, phosphatidylinositol 4,5-bisphosphate; p70S6K, p70 ribosomal S6 kinase.

Fig. 3. Physiological actions of the apelin system in different organs and tissues.

Activation of the apelin receptor results in a broad range of physiological effects in central and peripheral tissues. Within the vasculature, the apelin system promotes vasodilatation, subsequent lowering of blood pressure and angiogenesis and might also have antithrombotic effects. Apelin is a potent inotrope that increases myocardial Ca²⁺ sensitivity and reduces cardiac preload and afterload. It also increases the conduction velocity within cardiomyocytes, has anti-arrhythmic effects and reduces myocardial hypertrophy and fibrosis. In the kidney, activation of the apelin system increases renal blood flow and diuresis and reduces inflammation and fibrosis. The apelin system also has a central role in the regulation of fluid homeostasis: apelin inhibits hypothalamic vasopressin release and reduces water intake. Finally, the apelin system has a range of metabolic effects. It promotes brown adipogenesis and mitochondrial biogenesis in white adipose tissue, increases muscle glucose uptake and utilization and increases insulin sensitivity.

Fig. 4. The actions of apelin in the nephron.

a | Apelin acts at the afferent and efferent arterioles to promote vasodilatation via production of nitric oxide (NO), opposing the action of angiotensin II (Ang II). b | Increased vasodilatation at the efferent arteriole directly increases blood flow through the vasa recta, leading to increased medullary blood flow and promoting diuresis. c | The action of apelin counteracts vasopressin signalling in the kidney tubules. In the principal cells of the collecting duct, apelin prevents vasopressin-induced translocation of aquaporin 2 (AQP2) channels to the apical membrane and therefore prevents water reabsorption. AT₁ receptor, type 1 angiotensin II receptor; AVP, arginine vasopressin; Gi, inhibitory G protein α-subunit; Gs, stimulatory G protein α-subunit; V2R, vasopressin v2 receptor.