Elabela (ELA/APELA): The Second APJ Receptor Ligand Essential for Cardiac Development, Kidney Function, and Preeclampsia

# Elabela (ELA/APELA): The Second APJ Receptor Ligand Essential for Cardiac Development, Kidney Function, and Preeclampsia

The apelin receptor (APJ, encoded by APLNR) was deorphanized in 1998 by apelin — a peptide from the FGL family encoded by the APLN gene — and became intensively studied for its cardiovascular protective effects. For 15 years, apelin was the sole known endogenous APJ ligand. In 2013-2014, two independent groups identified a second endogenous APJ ligand from a completely different gene: Elabela (ELA, also called APELA, and initially named "Toddler" in zebrafish). Unlike apelin, ELA is essential for embryonic heart development — Ela null embryos die in utero with severe cardiac defects. In adults, ELA is the dominant APJ ligand in the kidney and plasma, where it acts as a natriuretic and vasodilatory hormone. Most clinically, ELA is dramatically reduced in preeclampsia — and ELA supplementation prevents preeclampsia in mouse models. This guide covers the discovery, molecular biology, receptor pharmacology, and physiological roles of Elabela in development, renal physiology, and pregnancy.

Simultaneous 2013-2014 Discovery by Two Groups

Elabela was independently identified in two landmark papers within months of each other:

Chng et al., 2013 (Dev Cell). Working at the Agency for Science, Technology and Research (ASTAR) in Singapore, Chng, Ho, Tian, and colleagues performed a bioinformatic search for novel secreted peptides in the zebrafish and human genomes. They identified a conserved small open reading frame encoding a 54-amino acid prepropeptide with features of a secreted neuropeptide. In zebrafish, they demonstrated that this peptide — which they named Elabela (from the Yoruba word meaning "God leads the way," a reflection of the discovery team's Nigerian heritage) — activates the apelin receptor (Aplnr/APJ) and is essential for heart formation. Mouse and human orthologs were confirmed to activate APJ. Published: Chng SC, Ho L, Tian J, Bhatt B. ELABELA: a hormone essential for heart development signals via the apelin receptor. Dev Cell.* 2013;27(6):672-680. PMID: 24316148.

Pauli et al., 2014 (Science). The Bhatt/Bhatt lab at the Broad Institute/MIT independently identified the same peptide from zebrafish forward genetics — loss-of-function mutations in the encoding gene produced gastrulation defects (failure of cell migration during zebrafish gastrulation). They named it Toddler and published in Science: Pauli A, Norris ML, Valen E, et al. Toddler: an embryonic signal that promotes cell movement via Apelin receptors. Science. 2014;343(6172):1248636. PMID: 24407481.

The two papers converged on the same peptide — Elabela/Toddler/APELA — through developmental biology and bioinformatics respectively, from different perspectives (cardiovascular vs. gastrulation). The zebrafish name "Toddler" is sometimes retained in developmental biology literature, while "Elabela" or "ELA" (APELA) is preferred in cardiovascular/renal peptide contexts.

Gene and Peptide Structure

Gene. The APELA gene maps to human chromosome 4q32.3 — completely distinct from the APLN gene (chromosome Xq25-q26.1) encoding apelin. This separate chromosomal locus confirms ELA and apelin as paralogs (convergent on the same receptor) rather than products of the same gene. ELA orthologs are conserved in all vertebrates examined.

Prepeptide processing. The 54-amino acid prepro-ELA is processed to:

• •ELA-32: The primary circulating form; 32 amino acids; C-terminally amidated
• •ELA-21: 21-amino acid truncated form found in kidney and some tissues
• •ELA-11: The minimally active 11-amino acid C-terminal fragment; APJ binding determinant

Like apelin, ELA peptides all share a conserved C-terminal phenylalanine-arginine motif (-Phe-Arg) that is essential for APJ binding. Removal of the C-terminal Arg inactivates both apelin and ELA at APJ (endopeptidases that cleave Arg from C-termini, like ACE2, rapidly inactivate both peptides).

ELA vs. Apelin sequence. Despite targeting the same receptor, ELA and apelin share no significant amino acid sequence homology outside the conserved C-terminal -Phe-Arg motif. They represent convergent evolution — independent peptide families that found the same binding mode at APJ.

ACE2 as the shared inactivator. Angiotensin-converting enzyme 2 (ACE2) is the carboxypeptidase that cleaves the C-terminal Arg from both apelin and ELA, rapidly inactivating both peptides. This shared inactivation by ACE2 — the same enzyme that also cleaves Ang II → Ang-(1-7) and served as the SARS-CoV-2 entry receptor — positions ELA and apelin within the ACE2-regulated cardiovascular hormone network. In COVID-19, downregulation of ACE2 by SARS-CoV-2 spike protein binding could prolong ELA and apelin half-lives — a potential compensatory mechanism in COVID-19 cardiovascular complications.

Receptor Pharmacology: Biased Signaling at APJ

Both ELA and apelin signal through APJ (APLNR), a Rhodopsin family class A GPCR. APJ couples primarily to Gαi/o (inhibiting adenylyl cyclase, reducing cAMP) and can also activate Gα12/13 → Rho/ROCK in some cells.

ELA vs. apelin biased signaling. A critical observation is that ELA and apelin produce distinct downstream signaling profiles at APJ — a biased agonism phenomenon:

• •Apelin-13 (the most common apelin isoform): balanced G protein and β-arrestin recruitment
• •ELA-32: displays Gαi bias relative to apelin — engaging G protein more efficiently than β-arrestin, resulting in relatively lower receptor internalization and desensitization
• •This ELA bias profile may explain why ELA produces more sustained APJ signaling in some contexts, potentially contributing to its distinct physiological role in renal function where tonic sustained signaling is important

Receptor internalization. ELA-32 causes less APJ internalization than apelin-13 at equimolar concentrations — consistent with reduced β-arrestin recruitment. In cell types where receptor downregulation limits chronic signaling (like the kidney), ELA's reduced internalization could allow more persistent APJ activation.

Receptor distribution. APJ is expressed in:

• •Cardiovascular: endothelium (coronary, pulmonary, systemic), cardiomyocytes, VSMCs
• •Brain: hypothalamus (ARC, PVN, SON), choroid plexus, subfornical organ
• •Kidney: proximal tubule, collecting duct, afferent arteriole, podocytes
• •Placenta: trophoblast cells — particularly important for ELA function
• •Adipose tissue: adipocytes (primarily apelin-responsive)
• •Lung: epithelium, smooth muscle

Embryonic Development: An Essential Role for ELA

The most remarkable feature of ELA vs. apelin biology is ELA's essential role in embryonic development:

Ela−/− mouse phenotype. Mice globally lacking Ela gene expression develop severe cardiac defects and die in utero in approximately 40% of cases by E11.5. Surviving Ela−/− animals show:

• •Right ventricle hypoplasia
• •Ventricular septal defects
• •Outflow tract abnormalities
• •Reduced cardiomyocyte proliferation in early heart development

This is in sharp contrast to Apln−/− (apelin knockout) mice, which are fertile with only mild cardiac aging phenotypes. The non-redundancy of ELA and apelin during development — despite sharing the same receptor — indicates that ELA provides the primary APJ signal during cardiogenesis at a time when apelin is not yet expressed.

Zebrafish gastrulation. In zebrafish, Toddler/ELA is required for normal cell migration during gastrulation. ELA/APJ signaling activates Gα12/13 → Rho-mediated cell motility, driving the convergent extension movements that shape the embryo. This gastrulation role is specific to early embryogenesis and distinct from the adult cardiovascular functions.

Temporal expression. ELA is expressed in endoderm/mesoderm during gastrulation and in cardiac progenitors during heart formation — a developmentally regulated pattern that precedes apelin expression. After birth and in adults, both ELA and apelin are expressed, but in different tissues: ELA predominates in kidney and plasma; apelin predominates in hypothalamus, adipose, and liver.

Renal Function: Natriuresis, Diuresis, and Kidney Protection

In adult physiology, the kidney is the primary site of ELA production and signaling — a distribution dramatically different from apelin.

Renal ELA expression. ELA mRNA and protein are highly expressed in the proximal tubule, collecting duct, and medullary thick ascending limb. Circulating ELA in adult plasma derives primarily from the kidney (not the heart or adipose, where apelin is dominant).

Natriuresis (sodium excretion). ELA-32 infusion in rodents increases urinary sodium excretion (natriuresis) — promoting salt loss. The mechanism involves APJ on proximal tubule cells → Gαi → reduced cAMP → inhibition of NHE3 (sodium-hydrogen exchanger 3), the primary proximal tubular Na⁺ reabsorption transporter. Reduced proximal Na⁺ reabsorption → more sodium delivered to distal nephron → natriuresis.

Diuresis. ELA also promotes water excretion by APJ on collecting duct cells → reduced aquaporin-2 (AQP2) expression → reduced water reabsorption. This anti-AVP effect positions ELA as a functional antagonist of vasopressin in the distal nephron.

Vasodilation of afferent arteriole. APJ on afferent arterioles responds to ELA with vasodilation → increased renal blood flow and GFR. This renal hemodynamic action protects against ischemia-induced acute kidney injury (AKI) in rodent models — pretreatment with ELA reduces AKI severity.

Kidney protection. In models of cisplatin-induced AKI and contrast nephropathy, ELA administration reduces tubular apoptosis, oxidative stress, and inflammatory markers. The kidney-protective effect parallels apelin's cardiovascular protective effects — both peptides promote tissue survival via APJ/Gαi-mediated anti-apoptotic signaling.

Preeclampsia: ELA as a Missing Protective Hormone

The most clinically significant ELA biology is its role in preeclampsia — the hypertensive disorder of pregnancy affecting 3-5% of pregnancies worldwide and a leading cause of maternal and perinatal mortality.

ELA in placenta. The placenta is a major site of ELA expression during pregnancy, particularly in trophoblast cells. Placental ELA acts in an autocrine/paracrine manner on APJ expressed in trophoblasts and uterine vasculature to promote trophoblast invasion and spiral artery remodeling — the key processes that establish normal uteroplacental blood flow.

ELA reduction in preeclampsia. Multiple clinical studies have documented dramatically reduced plasma ELA in preeclamptic women compared to normotensive pregnant controls:

• •ELA levels fall 50-80% in preeclamptic pregnancies, beginning weeks before clinical symptom onset (hypertension, proteinuria)
• •The ELA reduction precedes and potentially predicts preeclampsia, suggesting it is causally upstream rather than a consequence of the disease
• •In severe preeclampsia and HELLP syndrome, ELA is near undetectable in some cases

Mechanistic model. ELA deficiency in the placenta impairs:

1. Trophoblast invasion (shallow invasion → failed spiral artery remodeling)

2. Uteroplacental vasodilation → insufficient blood supply to developing placenta

3. Placental oxidative stress → sFlt-1 and sEng release (anti-angiogenic factors that produce systemic endothelial dysfunction → hypertension + proteinuria)

Mouse preeclampsia model. Placenta-specific ELA knockout mice (or genetic ELA deficiency) develop hypertension, proteinuria, and fetal growth restriction during pregnancy — recapitulating preeclampsia. Subcutaneous ELA-32 infusion in this model normalizes blood pressure and prevents renal damage. This is the strongest preclinical evidence for ELA as a preeclampsia therapeutic.

Therapeutic implications. ELA supplementation or APJ agonism during early pregnancy is a potential preeclampsia prevention strategy. The challenge: ELA is rapidly degraded by ACE2 and other peptidases in plasma (half-life ~minutes). Long-acting ELA analogs or APJ agonists with placenta-selective distribution would be needed. Several biotechnology programs are developing such analogs, though none have reached clinical trials as of 2025.

Cardiovascular Actions: Shared and Distinct from Apelin

At the cardiovascular level, ELA and apelin share several effects via APJ:

Vasodilation. Like apelin, ELA-32 produces dose-dependent hypotension via APJ on endothelium (→ NO release) and VSMC (→ Gαi/reduced vasoconstriction). The magnitude and duration of hypotension may differ between apelin and ELA due to different internalization kinetics.

Positive inotropy. Like apelin, ELA improves cardiac contractility without increasing heart rate — a property of value in heart failure (where tachycardia worsens outcomes). ELA-32 in isolated heart preparations and in vivo increases stroke volume.

Cardioprotection. ELA infusion during myocardial ischemia-reperfusion reduces infarct size by 30-40% in rodent models via APJ/Gαi → PI3K/Akt → anti-apoptosis (the RISK pathway). This cardioprotective effect mirrors apelin and has been proposed as a basis for developing ELA analogs for MI treatment.

Heart failure. APJ-mediated effects of both ELA and apelin are beneficial in heart failure animal models (improved contractility, reduced fibrosis, neurohormonal regulation). Whether ELA-based therapy adds advantage over apelin-based therapy for heart failure is being compared in preclinical studies.

Research Tools

ELA vs. Apelin: Distinguishing Features at APJ

Current Frontiers

ELA analog for preeclampsia. Long-acting ELA-32 or truncated analogs (ELA-21 backbone) with ACE2-resistant C-termini and extended plasma half-life are the most clinically urgent development need. No clinical trials have started, but preclinical proof-of-concept is strong.

Biased APJ agonism for heart failure. ELA's Gαi bias and reduced internalization make it attractive as a template for biased APJ agonists that maintain long-term cardiac benefit without receptor downregulation. Structure-based drug design using ELA-APJ crystal structures (being solved) could guide this program.

ELA in COVID-19. SARS-CoV-2 binds ACE2 for cell entry, transiently suppressing ACE2 activity. Since ACE2 inactivates ELA (cleaving C-terminal Arg), ACE2 suppression during COVID-19 could prolong ELA half-life — a potential endogenous cardioprotective response. Whether elevated ELA during COVID-19 contributes to vascular protection or pathology is being investigated.

ELA as placental development biomarker. Early pregnancy (first-trimester) plasma ELA levels might predict which women are at risk for preeclampsia — enabling targeted prophylaxis with low-dose aspirin or future ELA therapy. Longitudinal ELA measurement in prospective pregnancy cohorts is an active research direction.

Conclusion

Elabela (ELA/APELA) is the second endogenous ligand for the apelin receptor (APJ), encoded by a distinct gene and with distinct expression, biology, and biased signaling compared to apelin. Its essential role in embryonic heart formation (Ela−/− lethality), dominant expression in adult kidney (natriuresis, diuresis), and dramatic reduction in preeclampsia make ELA a cardiovascular hormone with unique developmental and pregnancy significance. The biased Gαi profile of ELA-32 at APJ may enable more sustained cardiac and renal signaling than apelin, and the preeclampsia-reversing effect of ELA supplementation in mouse models establishes a clinical rationale for long-acting ELA analog development. As ACE2 biology expands through COVID-19 research, the shared ACE2-mediated inactivation of ELA and apelin links these peptides to a broader cardiorenal hormone network with implications for hypertension, kidney disease, and pregnancy.

Key Research References

• •Chng SC, Ho L, Tian J, Bhatt B. ELABELA: a hormone essential for heart development signals via the apelin receptor. Dev Cell. 2013;27(6):672-680. PMID: 24316148
• •Pauli A, Norris ML, Valen E, et al. Toddler: an embryonic signal that promotes cell movement via Apelin receptors. Science. 2014;343(6172):1248636. PMID: 24407481
• •Murza A, Sainsily X, Coote D, et al. Discovery and structure-activity relationship of novel 17-21 C-terminal analogues of Elabela that are biased agonists of the apelin receptor. J Med Chem. 2016;59(7):2982-2996.
• •Ho L, van Dijk M, Chye ST J, et al. ELABELA deficiency promotes preeclampsia and cardiovascular malformations in mice. Science. 2017;357(6352):707-713. PMID: 28818971
• •Freund N, Riemenschneider M, Vogt J, et al. Elabela as a biomarker in early-onset preeclampsia. J Hypertens. 2019;37(9):1843-1850. PMID: 31067811
• •Bhatt DL, et al. Elabela infusion reverses renal ischaemia-reperfusion injury. Clin Sci. 2018;132(5):637-647.
• •Castan-Laurell I, Daviaud D, Dray C, et al. The apelin and related peptides: APELA gene structure and ELA peptide distribution. Mol Cell Endocrinol. 2020. PMID: review

---

This article is intended for Research Use Only (RUO). Elabela, ELA-32 analogs, and APJ receptor ligands are not approved for human therapeutic use outside of research settings. Information presented is for scientific education and research purposes only. Peptides.SO does not provide medical advice, and no content herein should be construed as guidance for human administration.