The Elabela-APJ axis attenuates sepsis-induced myocardial dysfunction by reducing pyroptosis by balancing the formation and degradation of autophagosomes.

BACKGROUND: Sepsis is a life-threatening severe inflammatory reaction caused by the host's dysregulated response to infection. Sepsis-induced myocardial dysfunction (SIMD) has been confirmed to occur in 50 % of patients with septic shock. Currently, the pathophysiological mechanism of SIMD is complex, and there is no targeted treatment. Elabela is another endogenous ligand of Aplnr (APJ). The protective effect of APJ on the heart has been proven. Elabela (Ela) has been shown to have a variety of cardiovascular protective effects. However, there are no studies demonstrating the protective effect of Ela-APJ axis on SIMD. MATERIALS AND METHODS: In vivo, C57BL/J mice were injected subcutaneously with 1 mg/kg/d Ela for 2 weeks, and in vitro, AC16 cells were treated with 1 µM Ela for 24 h. A 7-0 thread was used to ligate the distal end of the cecum, followed by puncture with a 20-gauge needle. Once a small amount of fluid leaks out, release the cecum back into the abdominal cavity. We measured the survival rates of the mice, performed ultrasound on their hearts, and evaluated the effects of the treatments. The serum and cell supernatant were extracted to detect myocardial injury markers and pyroptosis-related indicators. Western blotting was used to detect autophagy and pyroptosis-related protein. Molecular docking and other experiments were also used to detect changes in related proteins. RESULTS: In vivo, Ela significantly improved the survival rate of septic mice, improved cardiac function, and reduced the production of myocardial injury markers, oxidative stress and pyroptosis. In vitro, Ela unblocked autophagy flow by affecting TFEB transcription. Autophagy reduces inflammation and oxidative stress by selectively degrading inflammatory bodies and ultimately alleviates pyroptosis. CONCLUSION: We had demonstrated for the first time that in sepsis, Ela promoted the degradation of inflammasomes, reduced oxidative stress, and inhibited the occurrence of pyroptosis by unblocking autophagy flow.

Apelinergic system in acute kidney injury: Mechanistic insights and therapeutic potential.

Acute kidney injury (AKI) has emerged as a global health crisis, surpassing mortality rates associated with several cancers and heart failure. The lack of effective therapies, coupled with challenges in diagnosis and the high cost of kidney transplantation, underscores the urgent need to explore novel therapeutic targets and strategies for AKI. Understanding the intricate pathophysiology of AKI is paramount in this endeavor. The components of the apelinergic system-namely, apelin and elabela/toddler, along with their receptor-are prominently expressed in various kidney cells and have garnered significant attention in renal research. Recent studies have highlighted the renoprotective role of the apelinergic system in AKI. This system exerts its protective effects by modulating several pathophysiological processes, including reducing endoplasmic reticulum (ER) stress, improving mitochondrial dynamics, inhibiting inflammation and apoptosis, promoting diuresis through vasodilation of renal vasculature, and counteracting the effects of reactive oxygen species (ROS). Despite these advancements, the precise involvement of the apelinergic system in the progression of AKI remains unclear. Furthermore, the therapeutic potential of apelin-13 in AKI is not fully understood. This review aims to elucidate the role of the apelinergic system in AKI and its interactions with key pathomechanisms involved in the progression of AKI. Additionally, we discuss the current clinical status of exogenous apelin-13 therapy, providing insights that will guide future research on apelin against AKI.

Decreased plasma ELABELA level as a novel screening indicator for heart failure: a cohort and observational study.

The predictive power of B-type natriuretic peptide (BNP) and left ventricular ejection fraction (LVEF) is limited by its low specificity in patients with heart failure (HF). Discovery of more novel biomarkers for HF better diagnosis is necessary and urgent. ELABELA, an early endogenous ligand for the G protein-coupled receptor APJ (Apelin peptide jejunum, Apelin receptor), exhibits cardioprotective actions. However, the relationship between plasma ELABELA and cardiac function in HF patients is unclear. To evaluate plasma ELABELA level and its diagnostic value in HF patients, a total of 335 patients with or without HF were recruited for our monocentric observational study. Plasma ELABELA and Apelin levels were detected by immunoassay in all patients. Spearman correlation analysis was used to analyze the correlation between plasma ELABELA or Apelin levels and study variables. The receiver operating characteristic curves were used to access the predictive power of plasma ELABELA or Apelin levels. Plasma ELABELA levels were lower, while plasma Apelin levels were higher in HF patients than in non-HF patients. Plasma ELABELA levels were gradually decreased with increasing New York Heart Association grade or decreasing LVEF. Plasma ELABELA levels were negatively correlated with BNP, left atrial diameter, left ventricular end-diastolic diameter, left ventricular end-systolic diameter, and left ventricular posterior wall thickness and positively correlated with LVEF in HF patients. In contrast, the correlation between plasma Apelin levels and these parameters is utterly opposite to ELABELA. The diagnostic value of ELABELA, Apelin, and LVEF for all HF patients was 0.835, 0.673, and 0.612; the sensitivity was 62.52, 66.20, and 32.97%; and the specificity was 95.92, 67.23, and 87.49%, respectively. All these parameters in HF patients with preserved ejection fraction were comparable to those in total HF patients. Overall, plasma ELABELA levels were significantly reduced and negatively correlated with cardiac function in HF patients. Decreased plasma ELABELA levels may function as a novel screening biomarker for HF. A combined assessment of BNP and ELABELA may be a good choice to increase the accuracy of the diagnosis of HF.

Elabela mitigates the early stage of inflammation in sepsis by inhibiting pyroptosis.

OBJECTIVES: This study aims to investigate the potential therapeutic role of Elabela (ELA) in mitigating the sepsis-induced inflammatory storm, a phenomenon commonly associated with multiple organ dysfunction syndrome (MODS) and increased mortality. Our findings show the pathogenesis of sepsis, identifying ELA as a promising therapeutic target. METHODS: We conducted a comprehensive analysis of electronic medical records and blood samples from septic patients to assess the incidence of severe organ complication and characterize the inflammatory response. Subsequently, we measured the expression levels of ELA and various inflammatory factors in serum, and performed correlation analysis to explore the relationship between them, aiming to identify the cells and inflammatory pathways targeted by ELA. Furthermore, animal and cellular experiments were conducted to investigate the molecular mechanism underlying the therapeutic effect of ELA. RESULTS: Our findings revealed a higher prevalence of severe organ complications among septic patients, contributing to adverse prognoses and increased mortality. Notably, these patients exhibited significantly elevated levels of inflammatory cytokines such as interleukin-6 (IL-6) and interleukin-1ß (IL-1ß) in their sera, indicating a robust inflammatory response. Correlation analysis revealed a negative correlation between ELA and IL-1ß in septic patients. Through animal and cellular experiments, we demonstrated that ELA inhibits the cleavage of caspase-1 and gasdermin D (GSDMD), thereby attenuating pyroptosis and the inflammatory response. CONCLUSIONS: ELA is a promising therapeutic agent for mitigating the deleterious effects of sepsis. Its ability to inhibit macrophage pyroptosis and suppress the inflammatory response offers a novel approach.

Expression of the apelin receptor, a novel potential therapeutic target, and its endogenous ligands in diverse stem cell populations in human glioblastoma.

Glioblastoma multiforme (GBM) is one of the most common and lethal forms of brain cancer, carrying a very poor prognosis (median survival of ~15 months post-diagnosis). Treatment typically involves invasive surgical resection of the tumour mass, followed by radiotherapy and adjuvant chemotherapy using the alkylating agent temozolomide, but over half of patients do not respond to this drug and considerable resistance is observed. Tumour heterogeneity is the main cause of therapeutic failure, where diverse progenitor glioblastoma stem cell (GSC) lineages in the microenvironment drive tumour recurrence and therapeutic resistance. The apelin receptor is a class A GPCR that binds two endogenous peptide ligands, apelin and ELA, and plays a role in the proliferation and survival of cancer cells. Here, we used quantitative whole slide immunofluorescent imaging of human GBM samples to characterise expression of the apelin receptor and both its ligands in the distinct GSC lineages, namely neural-progenitor-like cells (NPCs), oligodendrocyte-progenitor-like cells (OPCs), and mesenchymal-like cells (MES), as well as reactive astrocytic cells. The data confirm the presence of the apelin receptor as a tractable drug target that is common across the key cell populations driving tumour growth and maintenance, offering a potential novel therapeutic approach for patients with GBM.

ELABELA-APJ Axis Enhances Mesenchymal Stem Cell Proliferation and Migration via the METTL3/PI3K/AKT Pathway.

Mesenchymal stem cells (MSCs) possess a strong therapeutic potential in regenerative medicine. ELABELA (ELA) is a 32 amino acid peptide that binds to the apelin peptide jejunum receptor (APJ) to regulate cell proliferation and migration. The aim of this study was to investigate the function of ELA vis-a-vis the MSC proliferation and migration, and further explore the underlying mechanism. We demonstrated that the exogenous supplement of ELA boosts the proliferation and migration ability of MSCs, alongside improved in vitro cell viability. These capabilities were rendered moot upon APJ knockdown. In addition, ELA (5-20 µM) was shown to upregulate the expression of METTL3 in a concentrationdependent pattern, a capacity which was suppressed by APJ reduction, whereas the downregulation of METTL3 expression blocked the beneficial effects induced by ELA. ELA was also observed to upregulate the phosphorylation level of AKT. This ELA-induced activation of the PI3K/AKT pathway, however, is inhibited with knockdown of METTL3. Our data indicate that ELA could act as a promoter of MSC proliferation and migration in vitro through the APJ receptor, something which might be attributed to the activation of the METTL3/PI3K/AKT signaling pathway. Therefore, ELA is a candidate for optimizing MSC-based cell therapy, while METTL3 is a potential target for its promoting action on MSCs.

Elabela ameliorates neuronal pyroptosis and mitochondrial fission via APJ/ZBP1 signaling in ischemic stroke.

Pyroptosis signifies a significant form of programmed neuronal demise subsequent to ischemic stroke. In our prior investigations, we demonstrated that the Elabela (ELA)-Apelin receptor (APJ) axis alleviated neuronal death by improving collateral circulation and mitigating ferroptosis in a murine model of middle cerebral artery occlusion (MCAO). However, the connection between ELA and neuronal pyroptosis remains further elucidation. Here, we observed an upregulation of ELA and APJ expression in both murine brain specimens and cultured HT-22 hippocampal neurons exposed to experimental ischemic stroke. ELA administration markedly diminished the infarct size in comparison to controls. ELA treatment ameliorated neurological deficits and anxiety-like symptoms in mice with stroke, concurrently inhibiting pyroptosis and mitochondria fission in neurons. Conversely, ELA knockdown yielded the opposite effects. Utilizing RNA-sequencing analysis, we identified a candidate for pyroptosis priming, Z-DNA-binding protein 1 (ZBP1), which was suppressed in ELA-treated HT-22 neurons during oxygen-glucose deprivation/reperfusion (OGD/R). Subsequent co-immunoprecipitation analyses demonstrated the binding between APJ and ZBP1. Specifically, APJ suppressed ZBP1 to inhibit NLRP3 inflammasome activation and dynamin-related protein 1-mediated mitochondrial fission in neurons. In summary, our findings suggest that ELA functions as a stroke-induced signal limiting neuronal pyroptosis and mitochondrial fission via APJ/ZBP1 signaling, thereby underscoring ELA as a potential therapeutic target for ischemic stroke treatment.

Endothelial ELABELA improves post-ischemic angiogenesis by upregulating VEGFR2 expression.

BACKGROUND: Post-ischemic angiogenesis is critical for perfusion recovery and tissue repair. ELABELA (ELA) plays an essential role in embryonic heart development and vasculogenesis. However, the mechanism of ELA on post-ischemic angiogenesis is poorly characterized. METHODS: We first assessed ELA expression after hind limb ischemia (HLI) in mice. We then established a HLI model in tamoxifen-inducible endothelial-ELA-specific knockout mice (ELAECKO) and assessed the rate of perfusion recovery, capillary density, and VEGFR2 pathway. Knockdown of ELA with lentivirus or siRNA and exogenous addition of ELA peptides were employed to analyze the effects of ELA on angiogenic capacity and VEGFR2 pathway in endothelial cells in vitro. The serum levels of ELA in healthy people and patients with type 2 diabetes mellitus (T2DM) and diabetic foot ulcer (DFU) were detected by a commercial ELISA kit. RESULTS: In murine HLI models, ELA was significantly up-regulated in the ischemic hindlimb. Endothelial-specific deletion of ELA impaired perfusion recovery and angiogenesis. In physiologic conditions, no significant difference in VEGFR2 expression was found between ELAECKO mice and ELAWT mice. After ischemia, the expression of VEGFR2, p-VEGFR2, and p-AKT was significantly lower in ELAECKO mice than in ELAWT mice. In cellular experiments, the knockdown of ELA inhibited endothelial cell proliferation and tube formation, and the addition of ELA peptides promoted proliferation and tube formation. Mechanistically, ELA upregulated the expression of VEGFR2, p-VEGFR2, and p-AKT in endothelial cells under hypoxic conditions. In clinical investigations, DFU patients had significantly lower serum levels of ELA compared to T2DM patients. CONCLUSION: Our results indicated that endothelial ELA is a positive regulator of post-ischemic angiogenesis via upregulating VEGFR2 expression. Targeting ELA may be a potential therapeutic option for peripheral arterial diseases.

Serum Elabela expression is decreased in hypertensive patients and could be associated with the progression of hypertensive renal damage.

BACKGROUND: Elabela, a recently discovered hormonal peptide containing 32 amino acids, is a ligand for the apelin receptor. It can lower blood pressure and attenuate renal fibrosis. However, the clinicopathological relationship between Elabela level and renal damage caused by benign hypertension (BHT) and malignant hypertension (MHT) has not been elucidated. Therefore, we investigated the clinicopathological correlation between serum Elabela level and renal damage caused by BHT and MHT. METHODS: The participants comprised 50 patients and 25 age-matched healthy adults. The 50 patients were separated into two groups: MHT (n = 25) and BHT groups (n = 25). We analyzed their medical histories, demographics, and clinical examinations, including physical and laboratory tests. RESULTS: The results showed that serum Elabela level decreased gradually with a continuous increase in blood pressure from the healthy control group, BHT, to MHT. Moreover, Elabela levels negatively correlated with BMI (R = - 0.27, P = 0.02), SBP (r = - 0.64, P < 0.01), DBP (r = - 0.58, P < 0.01), uric acid (r = - 0.39, P < 0.01), bun (r = - 0.53, P < 0.01), and Scr (r = - 0.53 P < 0.01) but positively correlated with eGFR (r = 0.54, P < 0.01). Stepwise multivariate linear regression analysis showed that SBP was the variable most related to Elabela (t = - 5.592, P < 0.01). CONCLUSIONS: Serum Elabela levels decreased in patients with hypertension, especially malignant hypertension, and has the potential to be a marker of hypertension-related kidney damage.

Influence of the Apelinergic System on Conduction Disorders in Patients after Myocardial Infarction.

BACKGROUND: There is a growing body of evidence for an important role of the apelinergic system in the modulation of cardiovascular homeostasis. The aim of our study was to (1) examine the relationship between apelin serum concentration at index myocardial infarction (MI) and atrioventricular conduction disorders (AVCDs) at 12-month follow-up, and (2) investigate the association between initial apelin concentration and the novel marker of post-MI scar (Q/QRS ratio) at follow-up. METHODS: In 84 patients with MI with complete revascularization, apelin peptide serum concentrations for apelin-13, apelin-17, elabela (ELA) and apelin receptor (APJ) were measured on day one of hospitalization; at 12-month follow-up, 54 of them underwent thorough examination that included 12-lead electrocardiography (ECG), Holter ECG monitoring and echocardiography. RESULTS: The mean age was 58.9 years. At 12-month follow-up, AVCDs were diagnosed in 21.4% of subjects, with AV first-degree block in 16.7% and sinoatrial arrest in 3.7%. ELA serum concentration at index MI correlated positively with the occurrence of AVCD (p = 0.003) and heart rate (p = 0.005) at 12-month follow-up. The apelin-13 serum concentration at index MI correlated negatively with the Q/QRS ratio. CONCLUSIONS: The apelin peptide concentration during an acute phase of MI impacts the development of AVCD and the value of Q/QRS ratio in MI survivors.

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

ELABELA (ELA), an endogenous ligand of the apelin receptor (also known as apelin peptide jejunum [APJ]), has been shown to decrease in the plasma of patients with diabetic kidney disease (DKD). In the current study, we explored the potential function as well as the underlying mechanisms of ELA in DKD. We first found that the ELA levels were decreased in the kidneys of DKD mice. Then, we found that ELA administration mitigated renal damage and downregulated the expression of fibronectin, collagen Ⅳ, and transforming growth factor-ß1 in the db/db mice and the high glucose cultured HK-2 cells. Furthermore, the autophagy markers, Beclin-1 and LC3-Ⅱ/LC3-Ⅰ ratio, were significantly impaired in DKD, but the ELA treatment reversed these alterations. Mechanistically, the inhibitory effects of ELA on the secretion of fibrosis-associated proteins in high glucose conditions were blocked by pretreatment with 3-methyladenine (an autophagy inhibitor). In summary, these in vivo and in vitro results demonstrate that ELA effectively protects against DKD by activating high glucose-inhibited renal tubular autophagy, potentially serving as a novel therapeutic candidate for DKD.

Advances in the study of ELABELA in renal physiological functions and related diseases.

ELABELA (ELA), also known as Toddler or Apela, is a novel endogenous ligand of the angiotensin receptor AT1-related receptor protein (APJ). ELA is highly expressed in human embryonic, cardiac, and renal tissues and involves various biological functions, such as embryonic development, blood circulation regulation, and maintaining body fluid homeostasis. ELA is also closely related to the occurrence and development of acute kidney injury, hypertensive kidney damage, diabetic nephropathy, renal tumors, and other diseases. Understanding the physiological role of ELA and its mechanism of action in kidney-related diseases would provide new targets and directions for the clinical treatment of kidney diseases.

A promising therapeutic peptide and preventive/diagnostic biomarker for age-related diseases: The Elabela/Apela/Toddler peptide.

Elabela (ELA), Apela or Toddler peptide is a hormone peptide belonging to the adipokine group and a component of apelinergic system, discovered in 2013-2014. Given its high homology with apelin, the first ligand of APJ receptor, ELA likely mediates similar effects. Increasing evidence shows that ELA has a critical function not only in embryonic development, but also in adulthood, contributing to physiological and pathological conditions, such as the onset of age-related diseases (ARD). However, still little is known about the mechanisms and molecular pathways of ELA, as well as its precise functions in ARD pathophysiology. Here, we report the mechanisms by which ELA/APJ signaling acts in a very complex network of pathways for the maintenance of physiological functions of human tissue and organs, as well as in the onset of some ARD, where it appears to play a central role. Therefore, we describe the possibility to use the ELA/APJ pathway, as novel biomarker (predictive and diagnostic) and target for personalized treatments of ARD. Its potentiality as an optimal peptide candidate for therapeutic ARD treatments is largely described, also detailing potential current limitations.

Predicting late-onset preeclampsia by detecting ELABELA content using an immunochromatographic colloidal gold test strip: Blood ELABELA content predicts the risk of pre-eclampsia.

Preeclampsia is a pregnancy disorder that seriously affects the outcome of mothers and infants and lacks effective prediction and diagnosis methods. ELABELA is the second endogenous ligand of the apelin receptor (APJ) and is associated with the pathogenesis of preeclampsia. In a previous study, the authors found that the downregulation of ELABELA expression is closely related to late-onset preeclampsia, which may be a marker for the clinical diagnosis of late-onset preeclampsia. In this study, the authors again collected 120 maternal blood samples, including 60 pregnant women with a medical diagnosis of late-onset preeclampsia. ELISA results showed that the serum ELABELA concentration in late-onset preeclampsia pregnant women (12.57 ± 7.77 ng/mL) was significantly lower than that in normal pregnant women (36.99 ± 23.58 ng/mL), which was consistent with previously reported results. Therefore, the authors used an ELABELA monoclonal antibody to label four colloidal gold nanoparticles with different diameters (15, 30, 55, and 150 nm) and developed a transverse-flow immunochromatographic band for the rapid and accurate detection of serum ELABELA levels. The strip test shows that colloidal gold with a diameter of 30 nm can be used as a good ELABELA detection marker and had more than 90% positive detection effect. Therefore, the authors hope that the colloidal gold strip with ELABELA as the diagnostic index developed by us will be popularized and applied in clinical diagnosis.

Therapeutic potential of apelin and Elabela in cardiovascular disease.

Apelin and Elabela (Ela) are peptides encoded by APLN and APELA, respectively, which act on their receptor APJ and play crucial roles in the body. Recent research has shown that they not only have important effects on the endocrine system, but also promote vascular development and maintain the homeostasis of myocardial cells. From a molecular biology perspective, we explored the roles of Ela and apelin in the cardiovascular system and summarized the mechanisms of apelin-APJ signaling in the progression of myocardial infarction, ischemia-reperfusion injury, atherosclerosis, pulmonary arterial hypertension, preeclampsia, and congenital heart disease. Evidences indicated that apelin and Ela play important roles in cardiovascular diseases, and there are many studies focused on developing apelin, Ela, and their analogues for clinical treatments. However, the literature on the therapeutic potential of apelin, Ela and their analogues and other APJ agonists in the cardiovascular system is still limited. This review summarized the regulatory pathways of apelin/ELA-APJ axis in cardiovascular function and cardiovascular-related diseases, and the therapeutic effects of their analogues in cardiovascular diseases were also included.

Cardiovascular aspects of ELABELA: A potential diagnostic biomarker and therapeutic target.

ELABELA, an early endogenous ligand for the G protein-coupled receptor APJ (apelin peptide jejunum, apelin receptor), has been known as an important regulator in cardiovascular homeostasis and may be a novel therapeutic target for multiple cardiovascular diseases (CVDs). At the physiological level, ELABELA exhibits angiogenic and vasorelaxant effects and is essential for heart development. At the pathological level, circulating ELABELA levels may be a novel diagnostic biomarker for various CVDs. ELABELA peripherally displays antihypertensive, vascular-protective, and cardioprotective effects, whereas central administration of ELABELA elevated BP and caused cardiovascular remodeling. This review highlights the physiological and pathological roles of ELABELA in the cardiovascular system. Enhancement of the peripheral ELABELA may be a promising pharmacological therapeutic strategy for CVDs.

The impact of the apelinergic system in coronary collateral formation.

Background: This study aims to examine the relationship between the development of coronary collateral circulation and serum elabela levels. Methods: Between January 2020 and December 2021, a total of 50 control individuals (29 males, 21 females; mean age: 63.2±10.0 years; range, 52 to 73 years) with no significant coronary artery disease as confirmed by angiography (Group 1) and 100 patients (55 males, 45 females; mean age: 66.6±9.6 years; range, 56 to 75 years) with coronary artery disease were included. The patients were further divided into two equal groups according to the Rentrop classification as poor (Group 2) and good coronary collateral circulation (Group 3). All groups were compared in terms of several parameters, particularly serum elabela levels. Results: Serum elabela levels were found to be statistically higher in the group with good collateral than the other groups (p<0.05). Low serum elabela levels increased the risk of developing weak collaterals by 2.43 times. Conclusion: The elabela protein is directly related to good collateral development and can be considered a potential agent for treatment.

Tubular Elabela-APJ axis attenuates ischemia-reperfusion induced acute kidney injury and the following AKI-CKD transition by protecting renal microcirculation.

Rationale: Ischemia-reperfusion injury (I/R) is a common cause of acute kidney injury (AKI). Post-ischemic recovery of renal blood supply plays an important role in attenuating injury. Exogenous application of elabela (ELA) peptides has been demonstrated by us and others to alleviate AKI, partly through its receptor APJ. However, the endogenous role of ELA in renal I/R remains unclear. Methods: Renal tubule specific ELA knockout (ApelaKsp KO) mice challenged with bilateral or unilateral I/R were used to investigate the role of endogenous ELA in renal I/R. RNA-sequencing analysis was performed to unbiasedly investigate altered genes in kidneys of ApelaKsp KO mice. Injured mice were treated with ELA32 peptide, Nω-hydroxy-nor-L-arginine (nor-NOHA), prostaglandin E2 (PGE2), Paricalcitol, ML221 or respective vehicles, individually or in combination. Results: ELA is mostly expressed in renal tubules. Aggravated pathological injury and further reduction of renal microvascular blood flow were observed in ApelaKsp KO mice during AKI and the following transition to chronic kidney disease (AKI-CKD). RNA-seq analysis suggested that two blood flow regulators, arginine metabolizing enzyme arginase 2 (ARG2) and PGE2 metabolizing enzyme carbonyl reductases 1 and 3 (CBR1/3), were altered in injured ApelaKsp KO mice. Notably, combination application of an ARG2 inhibitor nor-NOHA, and Paricalcitol, a clinically used activator for PGE2 synthesis, alleviated injury-induced AKI/AKI-CKD stages and eliminated the worst outcomes observed in ApelaKsp KO mice. Moreover, while the APJ inhibitor ML221 blocked the beneficial effects of ELA32 peptide on AKI, it showed no effect on combination treatment of nor-NOHA and Paricalcitol. Conclusions: An endogenous tubular ELA-APJ axis regulates renal microvascular blood flow that plays a pivotal role in I/R-induced AKI. Furthermore, improving renal blood flow by inhibiting ARG2 and activating PGE2 is an effective treatment for AKI and prevents the subsequent AKI-CKD transition.

Elabela is a reliable biomarker for predicting early onset preeclampsia: A comparative study.

BACKGROUND: Preeclampsia (PE) is a multisystemic metabolic disease with an undetermined etiology. PE is a worldwide cause of maternal and perinatal morbidity, subdivided into early (EoPE) and late-onset (LoPE) according to 34 wk of gestation as a divider. Many researchers investigated biomarkers for predicting PE to halt its consequences on the feto-maternal outcome. Elabela (Ela) is a newly discovered peptide hormone that was implicated in PE pathogenesis. Earlier rodent studies discussed Ela's role in controlling blood pressure. Moreover, Ela deficiency was associated with PE development. AIM: To test whether plasma Ela could serve as a reliable marker for predicting PE based on the time of onset (EoPE vs LoPE) compared to age and body mass matched healthy controls since no definitive treatment exists for PE but to terminate a pregnancy. METHODS: This case-control study recruited (n = 90) pregnant who fulfilled inclusion criteria; they were allocated into three groups: EoPE (30/90) (< 34 wk of gestation); LoPE (30/90) (≥ 34 wk of gestation); and healthy pregnant (30/90). Demographic criteria; biochemical, hematological, and maternal plasma Ela levels were recorded for comparison. RESULTS: Serum Ela was significantly reduced in EoPE compared to LoPE and healthy controls (P = 0.0023). The correlation confirmed a strong inverse relationship with mean atrial blood pressure (r = -0.7, P < 0.001), while gestational age and platelets count showed a moderate correlation with (r = 0.4 with P < 0.0001). No correlation was confirmed between the body mass index (BMI) and urine albumin. The predictive ability of 25 centile serum Ela had an Odds ratio of 5.21, 95% confidence interval (1.28, 21.24), P = 0.02 for predicting EoPE. The receiver operator characteristic curve defined the Ela cutoff value at > 9.156 with 96.7% and 93.3% sensitivity and specificity, P < 0.0001 in predicting EoPE. CONCLUSION: A strong correlation of serum Ela with PE parameters with excellent sensitivity and specificity in distinguishing EoPE independent of the BMI, age, and blood pressure which makes Ela a recommendable marker in screening. Further research is warranted to explore prognostic and therapeutic applications for Ela in PE.

The Apelinergic System in Pregnancy.

The apelinergic system is a highly conserved pleiotropic system. It comprises the apelin receptor apelin peptide jejunum (APJ) and its two peptide ligands, Elabela/Toddler (ELA) and apelin, which have different spatiotemporal localizations. This system has been implicated in the regulation of the adipoinsular axis, in cardiovascular and central nervous systems, in carcinogenesis, and in pregnancy in humans. During pregnancy, the apelinergic system is essential for embryo cardiogenesis and vasculogenesis and for placental development and function. It may also play a role in the initiation of labor. The apelinergic system seems to be involved in the development of placenta-related pregnancy complications, such as preeclampsia (PE) and intrauterine growth restriction, but an improvement in PE-like symptoms and birth weight has been described in murine models after the exogenous administration of apelin or ELA. Although the expression of ELA, apelin, and APJ is altered in human PE placenta, data related to their circulating levels are inconsistent. This article reviews current knowledge about the roles of the apelinergic system in pregnancy and its pathophysiological roles in placenta-related complications in pregnancy. We also discuss the challenges in translating the actors of the apelinergic system into a marker or target for therapeutic interventions in obstetrics.