Elabela Research Articles

ELABELA alleviates syncytiotrophoblast hypoxia/reoxygenation injury and preeclampsia-like symptoms in mice by reducing apoptosis

IntroductionPreeclampsia (PE) is associated with increased syncytiotrophoblast apoptosis. ELABELA (ELA) is a circulating hormone secreted by the placenta. Here, we investigated the involvement of ELA in the pathogenesis of PE. MethodsWe measured ELA expression in the placental villi of patients with severe PE and healthy controls. A cellular model of hypoxia and reoxygenation was used to simulate PE hypoxia, and changes in the proliferation and apoptosis of trophoblasts in response to different ELA concentrations were measured. In addition, we used NG-nitro-l-arginine methyl ester (l-NAME) to generate a mouse model of pregnancy-induced hypertension and explore whether ELA can improve the symptoms of PE. ResultsELA expression was decreased in severe PE. ELA promoted the proliferation of BeWo cells and improved the decreased cell proliferation rate after hypoxia/reoxygenation injury. ELA reversed the phenotypes of l-NAME-induced PE mice and regulated the expression of mouse placental apoptosis factors. DiscussionELA reduced apoptosis in BeWo cells and improved PE-like symptoms in mice, suggesting its value as a potential novel treatment for PE.

Structure-Activity Relationship and Bioactivity of Short Analogues of ELABELA as Agonists of the Apelin Receptor.

ELABELA (ELA) is the second endogenous ligand of the apelin receptor (APJ). Although apelin-13 and ELA both target APJ, there is limited information on structure-activity relationship (SAR) of ELA. In the present work, we identified the shortest bioactive C-terminal fragment ELA23-32, which possesses high affinity for APJ (Ki 4.6 nM) and produces cardiorenal effects in vivo similar to those of ELA. SAR studies on conserved residues (Leu25, His26, Val29, Pro30, Phe31, Pro32) show that ELA and apelin-13 may interact differently with APJ. His26 and Val29 emerge as important for ELA binding. Docking and binding experiments suggest that Phe31 of ELA may bind to a tight groove distinct from that of Phe13 of Ape13, while the Phe13 pocket may be occupied by Pro32 of ELA. Further characterization of signaling profiles on the Gαi1, Gα12, and β-arrestin2 pathways reveals the importance of aromatic residue at the Phe31 or Pro32 position for receptor activation.

ELABELA ameliorates hypoxic/ischemic-induced bone mesenchymal stem cell apoptosis via alleviation of mitochondrial dysfunction and activation of PI3K/AKT and ERK1/2 pathways

BackgroundMesenchymal stem cells (MSCs) have exerted their brilliant potential to promote heart repair following myocardial infarction. However, low survival rate of MSCs after transplantation due to harsh conditions with hypoxic and ischemic stress limits their therapeutic efficiency in treating cardiac dysfunction. ELABELA (ELA) serves as a peptide hormone which has been proved to facilitate cell growth, survival, and pluripotency in human embryonic stem cells. Although ELA works as an endogenous ligand of a G protein-coupled receptor APJ (Apelin receptor, APLNR), whether APJ is an essential signal for the function of ELA remains elusive. The effect of ELA on apoptosis of MSCs is still vague.ObjectiveWe studied the role of ELABELA (ELA) treatment on the anti-apoptosis of MSCs in hypoxic/ischemic (H/I) conditions which mimic the impaired myocardial microenvironment and explored the possible mechanisms in vitro.MethodsMSCs were obtained from donated rats weighing between 80~120 g. MSCs were exposed to serum-free and hypoxic (1% O2) environments for 24 h, which mimics hypoxic/ischemic damage in vivo, using serum-containing normoxic conditions (20% O2) as a negative control. MSCs that were exposed to H/I injury with ELA processing were treated by 5 μM of ELA. Cell viability and apoptosis of MSCs were evaluated by CCK8 and flow cytometry, respectively. Mitochondrial function of MSCs was also assessed according to mitochondrial membrane potential (MMP) and ATP content. The protein expression of key kinases of the PI3K/AKT and ERK1/2 signaling pathways involving t-AKT, p-AKT, t-ERK1/2, and p-ERK1/2, as well as apoptosis-related protein expression of Bcl-2, Bax, and cleaved Caspase 3, were monitored by Western blot.ResultsWe found that ELA treatment of H/I-induced MSCs improved overall cell viability, enhanced Bcl/Bax expression, and decreased Caspase 3 activity. ELA inhibited H/I-induced mitochondrial dysfunction by increasing ATP concentration and suppressing the loss of mitochondrial transmembrane potential. However, this anti-apoptotic property of ELA was restrained in APJ-silenced MSCs. Additionally, ELA treatment induced the phosphorylation of AKT and ERK, while the blockade of PI3K/AKT and ERK1/2 pathways with respective inhibitors, LY294002 and U0126, suppressed the action of ELA.ConclusionELA positively affected on the survival of MSCs and exhibited anti-apoptotic characteristics when exposed to hypoxic/ischemic condition in vitro. Also, the function of ELA was correlated with the APJ receptor, reduced mitochondrial damage, and activation of the PI3K/AKT and ERK1/2 signal axes.

Plasma levels of Elabela are associated with coronary angiographic severity in patients with acute coronary syndrome.

BackgroundElabela (ELA) was newly discovered as a novel endogenous ligand of the apelin receptor (APJ) which has demonstrated to be crucial for cardiovascular disease such as myocardial infarction, hypertension and heart failure. Previous experiments have revealed that ELA reduced arterial pressure and exerted positive inotropic effects on the heart. However, the role of plasma ELA levels in patients with acute coronary syndrome (ACS) and its relationship with severity of coronary arteries have not been investigated.MethodsTwo hundred and one subjects who were hospitalized for chest pain and underwent coronary angiography were recruited in this study. One hundred and seventy five patients were diagnosed with ACS and twenty-six subjects with negative coronary angiography were included in the control group. Plasma ELA levels, routine blood test, blood lipid, liver and kidney functions were measured. The number of coronary arteries and SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) score of coronary lesions were used to evaluate the extent of coronary artery stenosis.ResultsELA in patients with ACS was significantly higher than that in the control group (P < 0.01). There was no significant difference in plasma ELA levels among patients with single-, double- and triple-vessel diseases. However, in the generalized additive model (GAM), there was a threshold nonlinear correlation between the ELA levels and Syntax I score (P < 0.001). Plasma ELA levels were positively correlated with the Syntax I score when the ELA levels ranged from 63.47 to 85.49 ng/mL. There was no significant association between the plasma ELA levels and the extent of coronary artery stenosis when the ELA levels were less than 63.47 ng/mL or higher than 85.49 ng/mL.ConclusionThe present study demonstrates for the first time that plasma ELA levels are increased in patients with ACS. The rise in endogenous ELA levels was associated with severity of coronary stenosis and may be involved in the pathogenesis of ACS.

Elabela: A Novel Biomarker for Right Ventricular Pressure Overload in Children With Pulmonary Stenosis or Pulmonary Atresia With Intact Ventricular Septum.

Background: Assessing right ventricular overload in children is challenging. We conducted this study involving children with pulmonary valvular stenosis (PS) or pulmonary atresia with intact ventricular septum (PA/IVS) to evaluate the potential of a new endogenous ligand of apelin receptor, Elabela (ELA), as a potential biomarker for right heart overload.Methods: In this prospective cohort study, a total of 118 congenital heart diseases patients with right ventricle outflow tract obstruction were recruited from 2018 to 2019. Among them, 44 isolated PS and 7 PA/IVS patients were selected. Their venous blood was collected, and all patients underwent an echocardiographic examination. Among them, post-operative blood was collected from 24 patients with PS after percutaneous balloon pulmonary valvuloplasty. The plasma ELA concentration was measured using enzyme-linked immunosorbent assay.Results: The ELA was significantly associated with the peak transvalvular pulmonary gradient (r = −0.62; p = 0.02), thus reflecting the severity of PS or PA/IVS. The ELA significantly increased at 3 days after intervention, when mechanical obstruction of the right outflow tract was relieved. Based on the receiver-operator characteristic curve results, ELA could be a risk factor for duct dependence in patients with critical PS or PA/IVS who are younger than 6 months (AUC: 0.82).Conclusion: ELA concentration and severity of PS or PA/IVS had a significant negative correlation, indicating that ELA might be a novel biomarker for right ventricular afterload and reflect the immediate pressure changes in the right heart. Furthermore, ELA could predict duct-dependency in PS and PA/IVS patients, as valuable as classical echocardiographic indexes.

Association between ELABELA Serum Concentrations in First Trimester and Pregnancy-Induced Hypertension.

ELABELA (ELA) is considered to be implicated in the pathophysiology of preeclampsia (PE), since ELA-deficient mice exhibited PE-like symptoms and infusion of exogenous ELA normalized the gestational hypertension (GH) and proteinuria. However, no evidence show that circulating ELA is deficient in early placental development among women who destined to develop GH/PE. This nested case-control study was conducted to investigate the association between serum ELA concentration in early pregnancy and the risk of later GH/PE. Participants were recruited and sampled in 10-14+6 weeks of gestation. Definite GH/PE cases were matched 1 : 3 to controls with respect to age and gestational age. Serum concentration of ELA was measured using enzyme immunoassay. Women with later GH (N = 28) had a slightly lower median concentration of ELA (46.72 ng/mL versus 53.54 ng/mL), while those with later PE (N = 16) had a slightly higher median concentration of ELA (74.8 ng/mL versus 66.30 ng/mL) compared to the controls. Yet, both the increments did not reach statistically significant difference (GH: P = 0.380, PE: P = 0.799). ELA serum concentrations were unchanged in first trimester in women with GH/PE. Further studies are still needed to identify the dynamic changes in serum ELA concentrations during the whole pregnancy, especially in those with pregnancy-induced hypertensive disorders.

Fc-Elabela fusion protein attenuates lipopolysaccharide-induced kidney injury in mice.

Endotoxemia-induced acute kidney injury (AKI) is a common clinical condition that lacks effective treatments. Elabela (ELA) is a recently discovered kidney peptide hormone, encoded by the gene apela, and has been reported to improve cardio-renal outcomes in sepsis. However, ELA is a small peptide and is largely unsuitable for clinical use because of its short in vivo half-life. In the present study, we evaluated the potential renoprotective effects of a long-acting constant fragment (Fc)-ELA fusion protein in liposaccharide (LPS)-induced AKI in mice. LPS administration in mice for 5 days greatly lowered the gene expression of apela and impaired kidney function, as evidenced by elevated serum creatinine and the ratio of urine protein to creatinine. In addition, renal inflammation and macrophage infiltration were apparent in LPS-challenged mice. Treatment with the Fc-ELA fusion protein partially restored apela expression and attenuated the kidney inflammation. Moreover, LPS treatment induced reactive oxygen species (ROS) production and apoptosis in kidney HK-2 cells as well as in the mouse kidney, which were mitigated by ELA or Fc-ELA treatment. Finally, we found that ELA promoted the survival of HK-2 cells treated with LPS, and this action was abolished by LY204002, a PI3K/Akt inhibitor. Collectively, we have demonstrated that the Fc-ELA fusion protein has significant renoprotective activities against LPS-induced AKI in mice.

ELABELA improves endothelial cell function via the ELA-APJ axis by activating the PI3K/Akt signalling pathway in HUVECs and EA.hy926 cells.

Destruction of endothelial cells (ECs) function is involved in the structural and functional pathophysiological processes of preeclampsia (PE). Vascular endothelial injury may pre-exist for several years in women that develop PE and may pose increased risks for hypertension, coronary artery disease, and type-2 diabetes mellitus. Previous findings showed that Elabela (ELA), the endogenous ligand of the apelin (APJ) receptor expressed mainly on ECs, may play a protective role in early pregnancy and prevent PE. However, the exact functional role and molecular mechanisms of ELA are unclear. Here, we aimed to classify whether and how ELA improves EC function via the ELA-APJ axis. Two human umbilical vein endothelial cell (HUVEC) lines, namely HUVECs and EA.hy926, were treated with ELA, and then their cellular activities were studied by performing CCK-8 tests, scratch-wound analysis, and tube-formation assays. Doses of ELA exceeding 0.01μmol/L markedly improved the cell viability, migration, and tube formation ability of HUVECs and EA.hy926 cells. Western blot analysis indicated that the above effects caused by ELA were related to upregulation of the APJ receptor and activation of PI3K/Akt signalling. Further verification tests were performed using the PI3K inhibitor wortmannin, and the results illustrated that inhibiting PI3K/Akt signalling blocked the positive effects of ELA on EC function and APJ receptor expression. Taken together, our findings indicate that ELA may alter EC function via the ELA-APJ axis and PI3K/Akt signalling and that ELA shows promise for use in endothelial dysfunction therapy for preventing and treating PE.

ELABELA attenuates deoxycorticosterone acetate/salt-induced hypertension and renal injury by inhibition of NADPH oxidase/ROS/NLRP3 inflammasome pathway

ELABELA (ELA), a 32-residue hormone peptide abundantly expressed in adult kidneys, has been identified as a novel endogenous ligand for APJ/Apelin receptor. The aim of this study was to investigate the role of ELA in deoxycorticosterone acetate (DOCA)/salt-induced hypertension and further explore the underlying mechanism. In DOCA/salt-treated rats, the mRNA level of ELA greatly decreased in the renal medulla. Next, overexpression of ELA in the kidney was found to attenuate DOCA/salt-induced hypertension and renal injury, including lower blood pressure, reversed glomerular morphological damage, decreased blood urea nitrogen (BUN), and blocked the accumulation of fibrotic markers. Mechanistically, ELA overexpression inhibited renal nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and subsequent reactive oxygen species (ROS) production, thus resulted in the blockade of formation and activation of Nod-like receptor protein 3 (NLRP3) inflammasome. The inhibitory effects of ELA on Aldosterone-stimulated NADPH oxidase/ROS/NLRP3 inflammasome pathway were confirmed in the human renal tubular cells. Furthermore, our in vivo and in vitro results showed that the deficiency of the apelin receptor APJ did not influence the antihypertensive effect and blockage to NADPH oxidase/ROS/NLRP3 pathway of ELA. Moreover, in heterozygous ELA knockout mice (ELA+/−), the ELA deficiency remarkably accelerated the onset of DOCA/salt-induced hypertension. Our data demonstrate that ELA prevents DOCA/salt-induced hypertension by inhibiting NADPH oxidase/ROS/NLRP3 pathway in the kidney, which is APJ independent. Pharmacological targeting of ELA may serve as a novel therapeutic strategy for the treatment of hypertensive kidney disease.

The Elabela in hypertension, cardiovascular disease, renal disease, and preeclampsia: an update.

: Although considerable success has been shown for antihypertensive medications, the resistant hypertension and hypertension-related organ damages are still the important clinical issues and pose as high health and economic pressure. Therefore, novel therapeutic techniques and antihypertensive drugs are needed to advance more effective therapy of hypertension and hypertension-related disease to ameliorate mortality and healthcare costs worldwide. In this review, we highlight the latest progress in supporting the therapeutic potential of Elabela (ELA), a recently discovered early endogenous ligand for G-protein-coupled receptor apelin peptide jejunum, apelin receptor. Systemic administration of ELA exerts vasodilatory, antihypertensive, cardioprotective, and renoprotective effects, whereas central application of ELA increases blood pressure and causes cardiovascular remodeling primarily secondary to the hypertension. In addition, ELA drives extravillous trophoblast differentiation and prevents the pathogenesis of preeclampsia (a gestational hypertensive syndrome) by promoting placental angiogenesis. These findings strongly suggest peripheral ELA's therapeutic potential in preventing and treating hypertension and hypertension-related diseases including cardiovascular disease, kidney disease, and preeclampsia. Since therapeutic use of ELA is mainly limited by its short half-life and parenteral administration, it may be a clinical application candidate for the therapy of hypertension and its complications when fused with a large inert chemicals (e.g. polyethylene glycol, termed polyethylene glycol-ELA-21) or other proteins (e.g. the Fc fragment of IgG and albumin, termed Fc-ELA-21 or albumin-ELA-21), and new delivery methods are encouraged to develop to improve the efficacy of ELA fragments on apelin peptide jejunum or alternative unknown receptors.

MicroRNA-122 aggravates angiotensin II-mediated apoptosis and autophagy imbalance in rat aortic adventitial fibroblasts via the modulation of SIRT6-elabela-ACE2 signaling

Abnormal aortic adventitial fibroblasts (AFs) play essential roles in the development of vascular remodeling and disorders. Previous studies revealed that microRNA-122 (miR-122) levels were elevated in the aortic adventitia of hypertensive rats with vascular injury. Here, we aim to evaluate the biological effects and underlying mechanisms of miR-122 in rat AFs. Exposure to angiotensin II (ATII) in rat AFs resulted in decreased levels of sirtuin 6 (SIRT6), elabela (ELA), and angiotensin-converting enzyme 2 (ACE2). Additionally, stimulation with ATII contributed to a decline in autophagic flux and obvious increases in cellular migration, oxidative stress, and apoptosis, which were exacerbated by the transfection of miR-122-5p mimic but were rescued by miR-122-5p inhibitor, exogenous replenishment of ELA, and recombinant adeno-associated virus expressing SIRT6 (rAAV-SIRT6), respectively. Moreover, stimulation with miR-122-5p mimic led to a marked reduction in the levels of SIRT6 and ELA in rat AFs, which were elevated by stimulation with rAAV-SIRT6. Furthermore, miR-122-5p inhibitor-mediated pro-autophagic, anti-oxidant and anti-apoptotic effects in rat AFs were partially suppressed by 3-methyladenine, SIRT6 small interfering RNA (siRNA) and ELA siRNA, which were linked with the downregulation in the protein levels of LC3-II, beclin-1, and ACE2 and the upregulation of p62 expression and bax/bcl-2 ratio. Our findings indicated that miR-122-5p inhibition prevented ATII-mediated loss of autophagy, and the promotion of apoptosis and oxidative stress via activating the SIRT6-ELA-ACE2 signaling. MiR-122-5p may be a novel predictive biomarker of adventitial injury, and targeting the SIRT6-ELA-ACE2 signaling may have the potential therapeutic importance of controlling vascular remodeling and disorders.

Elabela levels in patients with type 2 diabetes: can it be a marker for diabetic nephropathy?

Elabela (ELA) is a hormone that is secreted at high levels in the kidneys of a healthy adult. This study aims to investigate whether serum ELA levels of patients with Type 2 Diabetes vary with the severity of renal damage. Our study included 50 healthy control subjects and 100 diabetic patients, who were categorized into groups based on urine albumin/creatinine ratios (ACR). Patients included in the study were assigned to four groups: Group 1 (healthy control), Group 2 (ACR<29mg/g), Group 3 (ACR=30-299 mg/g), and Group 4 (ACR>300 mg/g normal or high serum creatinine). Physical examination findings, demographic characteristics of the study group were recorded, and serum ELA levels and other laboratory parameters were assessed using appropriate methods. The results of the study indicated that ELA levels determined in healthy individuals gradually decreased through stages of normal albuminuria, microalbuminuria, and macroalbuminuria. Moreover, ELA had a significant negative correlation with LDL-C (r=-0.201, p=0.014), glucose (r=-0.437, P<0.001), retinopathy (r=-0.222, P=0.006), serum BUN (r=-0.161, P=0.049), and a positive correlation with eGFR (r=0.250, P=0.002). The fact that ELA levels are higher in healthy individuals compared to diabetic patients without microalbuminuria, and higher in diabetic patients without microalbuminuria compared to patients with advanced albuminuria and kidney damage, suggests that the ELA level can be an important clinical prognostic variable and even a promising agent for the treatment of diabetic nephropathy patients.

Elabela, Nitric Oxide and Apelin in Women with Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is a major health issue amid fertile-aged women in all society. Therefore, we investigated levels of Elabela (ELA), Apelin (APLN), and Nitric Oxide (NO) in women with and without PCOS, and to identify whether there is any association between ELA, APLN, NO and metabolic parameters. 27 PCOS and 30 control subjects were included. ELA, APLN and NO levels were analyzed by using enzyme linked immunosorbent assay. Both groups demonstrated no significant difference in terms of age and Body mass index (BMI), Insulin, HOMA-IR, Ferriman–Gallwey score, and free testosterone were significantly higher (p &lt; 0.05), whereas high-density lipoprotein (HDL), and estradiol (E2) levels were lower in women with the PCOS than that of controls. Lower ELA levels [(28.6 versus 39.4) ng/ml, p&lt;0.05], and lower NO [(194.8 versus 322.5) µmol/L, p &lt;0.001], and higher APLN levels [(478.7 versus 388.4) pg/ml, p &lt;0.05] were reported in PCOS patients compared to controls. ELA and NO are significantly down regulated while APLN (p&lt;0.05) is significantly up regulated (p&lt;0.05) in PCOS patients compared to controls. Based on the findings of this study, decreased ELA and NO, increased APLN levels may be considered as potential regulators of glucose and fat metabolism in PCOS patients. It was also assumed that early measurement of ELA, APLN and NO in PCOS cases might help to avoid the aggravation of PCOS.

Essential Role of the ELABELA-APJ Signaling Pathway in Cardiovascular System Development and Diseases

ELABELA (ELA), previously classified as a "noncoding" RNA, is a new endogenous peptidic ligand of apelin receptor (APJ/APLNR), a class A (rhodopsin-like) G protein-coupled receptor. It has been identified to play a crucial role in diverse biological processes, especially in the normal and pathological cardiovascular system. In comparison with APJ's first ligand apelin, ELA may play a key role at different time points or heart regions. In this review, we summarized the roles of the ELA-APJ signaling pathway in cardiovascular system development and diseases.

Circulating levels of Elabela and Apelin in the second and third trimesters of pregnancies with gestational diabetes mellitus

We design this study to detect levels of Elabela (ELA) and Apelin (APLN) in women with and without gestational diabetes mellitus (GDM) in the second and third trimesters, and to identify whether there is any association between ELA, APLN, and metabolic parameters. Seventy-nine GDM and 80 control subjects in the second trimester and 87 GDM and 88 healthy subjects in the third trimester were included. In the second trimester, lower ELA levels [(14.1 versus 16.9) ng/ml, p = .025] and higher APLN levels [(1021.8 versus 923.5) pg/ml, p = .046] were observed in GDM patients compared to controls. ELA levels were positively correlated with fasting plasma glucose (FPG) (r = 0.423, p < .001) in the control group, and APLN levels were negatively correlated with triglycerides (TG) (r = −0.251, p = .025) in the control group and total cholesterol (TC) (r = −0.227, p = .044) in the GDM group. ELA appeared to be related to glucose metabolism and APLN is involved in lipid metabolism during pregnancy. The expression of ELA is significantly downregulated from the second trimester to the third trimester.

ELABELA antagonizes intrarenal renin-angiotensin system to lower blood pressure and protects against renal injury.

Emerging evidence has demonstrated that (pro)renin receptor (PRR)-mediated activation of intrarenal renin-angiotensin system (RAS) plays an essential role in renal handling of Na+ and water balance and blood pressure. The present study tested the possibility that the intrarenal RAS served as a molecular target for the protective action of ELABELA (ELA), a novel endogenous ligand of apelin receptor, in the distal nephron. By RNAscope and immunofluorescence, mRNA and protein expression of endogenous ELA was consistently localized to the collecting duct (CD). Apelin was also found in the medullary CDs as assessed by immunofluorescence. In cultured CD-derived M1 cells, exogenous ELA induced parallel decreases of full-length PRR (fPRR), soluble PRR (sPRR), and prorenin/renin protein expression as assessed by immunoblotting and medium sPRR and prorenin/renin levels by ELISA, all of which were reversed by 8-bromoadenosine 3',5'-cyclic monophosphate. Conversely, deletion of PRR in the CD or nephron in mice elevated Apela and Apln mRNA levels as well as urinary ELA and apelin excretion, supporting the antagonistic relationship between the two systems. Administration of exogenous ELA-32 infusion (1.5 mg·kg-1·day-1, minipump) to high salt (HS)-loaded Dahl salt-sensitive (SS) rats significantly lowered mean arterial pressure, systolic blood pressure, diastolic blood pressure, and albuminuria, accompanied with a reduction of urinary sPRR, angiotensin II, and prorenin/renin excretion. HS upregulated renal medullary protein expression of fPRR, sPRR, prorenin, and renin in Dahl SS rats, all of which were significantly blunted by exogenous ELA-32 infusion. Additionally, HS-induced upregulation of inflammatory cytokines (IL-1β, IL-2, IL-6, IL-17A, IFN-γ, VCAM-1, ICAM-1, and MCP-1), fibrosis markers (TGF-β1, FN, Col1A1, PAI-1, and TIMP-1), and kidney injury markers (NGAL, Kim-1, albuminuria, and urinary NGAL excretion) were markedly blocked by exogenous ELA infusion. Together, these results support the antagonistic interaction between ELA and intrarenal RAS in the distal nephron that appears to exert a major impact on blood pressure regulation.

Changes in pregnancy-related serum biomarkers early in gestation are associated with later development of preeclampsia.

BackgroundPlacental protein expression plays a crucial role during pregnancy. We hypothesized that: (1) circulating levels of pregnancy-associated, placenta-related proteins throughout gestation reflect the temporal progression of the uncomplicated, full-term pregnancy, and can effectively estimate gestational ages (GAs); and (2) preeclampsia (PE) is associated with disruptions in these protein levels early in gestation; and can identify impending PE. We also compared gestational profiles of proteins in the human and mouse, using pregnant heme oxygenase-1 (HO-1) heterozygote (Het) mice, a mouse model reflecting PE-like symptoms.MethodsSerum levels of placenta-related proteins–leptin (LEP), chorionic somatomammotropin hormone like 1 (CSHL1), elabela (ELA), activin A, soluble fms-like tyrosine kinase 1 (sFlt-1), and placental growth factor (PlGF)–were quantified by ELISA in blood serially collected throughout human pregnancies (20 normal subjects with 66 samples, and 20 subjects who developed PE with 61 samples). Multivariate analysis was performed to estimate the GA in normal pregnancy. Mean-squared errors of GA estimations were used to identify impending PE. The human protein profiles were then compared with those in the pregnant HO-1 Het mice.ResultsAn elastic net-based gestational dating model was developed (R2 = 0.76) and validated (R2 = 0.61) using serum levels of the 6 proteins measured at various GAs from women with normal uncomplicated pregnancies. In women who developed PE, the model was not (R2 = -0.17) associated with GA. Deviations from the model estimations were observed in women who developed PE (P = 0.01). The model developed with 5 proteins (ELA excluded) performed similarly from sera from normal human (R2 = 0.68) and WT mouse (R2 = 0.85) pregnancies. Disruptions of this model were observed in both human PE-associated (R2 = 0.27) and mouse HO-1 Het (R2 = 0.30) pregnancies. LEP outperformed sFlt-1 and PlGF in differentiating impending PE at early human and late mouse GAs.ConclusionsSerum placenta-related protein profiles are temporally regulated throughout normal pregnancies and significantly disrupted in women who develop PE. LEP changes earlier than the well-established biomarkers (sFlt-1 and PlGF). There may be evidence of a causative action of HO-1 deficiency in LEP upregulation in a PE-like murine model.

Apelin/Elabela-APJ: a novel therapeutic target in the cardiovascular system.

Apelin and Elabela (ELA) are endogenous ligands of angiotensin domain type 1 receptor-associated proteins (APJ). Apelin/ELA-APJ signal is widely distributed in the cardiovascular system of fetuse and adult. The signal is involved in the development of the fetal heart and blood vessels and regulating vascular tension in adults. This review described the effects of apelin/ELA-APJ on fetal (vasculogenesis and angiogenesis) and adult cardiovascular function [vascular smooth muscle cell (VSMC) proliferation, vasodilation, positive myodynamia], and relative diseases [eclampsia, hypertension, pulmonary hypertension, heart failure (HF), myocardial infarction (MI), atherosclerosis, etc.] in detail. The pathways of apelin/ELA-APJ regulating cardiovascular function and cardiovascular-related diseases are summarized. The drugs developed based on apelin and ELA suggests APJ is a prospective strategy for cardiovascular disease therapy.

Serum elabela and apelin levels during different stages of chronic kidney disease

Purpose The association of serum elabela (ELA) and apelin with the progression of chronic kidney disease (CKD) is unknown. We determined if serum ELA and apelin levels were associated with CKD stage. Methods This observational study involved 60 CKD patients and 20 healthy, age-, race-, and gender-matched controls. The participants were grouped according to renal function as follows: normal control group, CKD1 group (stage-1 CKD, 20 patients), CKD3 group (stage-3 CKD, 20 patients), and CKD5 group (stage-5 CKD, 20 patients) in accordance with the Kidney Disease Outcomes – Quality Initiative criteria. We recorded the demographic, clinical, and biochemical data of all participants. Serum ELA and apelin levels were measured using commercially available enzyme-linked immunosorbent assays. Results Serum ELA levels gradually and significantly declined with decreases in the estimated glomerular filtration rate (eGFR). Serum ELA showed significant negative correlations with serum creatinine (r = −0.529, p < .001), blood urea nitrogen (r = −0.575, p < .001), systolic blood pressure (r = −0.455, p < .001), and diastolic blood pressure (r = −0.450, p < .001), and significant positive correlations with hemoglobin (r = 0.523, p < .001) and eGFR (r = 0.728, p < .001). Multiple regression analysis showed that eGFR independently influenced serum ELA levels. No significant association was found between serum apelin levels and CKD progression. Conclusion In CKD patients, serum ELA levels decreased with decreasing eGFR. This finding may provide a new target for the prediction, diagnosis, and staging of CKD.

Peptide hormone ELABELA enhances extravillous trophoblast differentiation, but placenta is not the major source of circulating ELABELA in pregnancy

Preeclampsia is a frequent gestational hypertensive disorder with equivocal pathophysiology. Knockout of peptide hormone ELABELA (ELA) has been shown to cause preeclampsia-like symptoms in mice. However, the role of ELA in human placentation and whether ELA is involved in the development of preeclampsia in humans is not yet known. In this study, we show that exogenous administration of ELA peptide is able to increase invasiveness of extravillous trophoblasts in vitro, is able to change outgrowth morphology and reduce trophoblast proliferation ex vivo, and that these effects are, at least in part, independent of signaling through the Apelin Receptor (APLNR). Moreover, we show that circulating levels of ELA are highly variable between women, correlate with BMI, but are significantly reduced in first trimester plasma of women with a healthy BMI later developing preeclampsia. We conclude that the large variability and BMI dependence of ELA levels in circulation make this peptide an unlikely candidate to function as a first trimester preeclampsia screening biomarker, while in the future administering ELA or a derivative might be considered as a potential preeclampsia treatment option as ELA is able to drive extravillous trophoblast differentiation.