ELABELA and an ELABELA Fragment Protect against AKI.
Chen Hong,Wang Lin,Wang Wenjun,Cheng Cheng,Zhang Yu,Zhou Yu,Wang Congyi,Miao Xiaoping,Wang Jiao,Wang Chao,Li Jianshuang,Zheng Ling,Huang Kun
Journal of the American Society of Nephrology : JASN
Renal ischemia-reperfusion (I/R) injury is the most common cause of AKI, which associates with high mortality and has no effective therapy. ELABELA (ELA) is a newly identified 32-residue hormone peptide highly expressed in adult kidney. To investigate whether ELA has protective effects on renal I/R injury, we administered the mature peptide (ELA32) or the 11-residue furin-cleaved fragment (ELA11) to hypoxia-reperfusion (H/R)-injured or adriamycin-treated renal tubular cells ELA32 and ELA11 significantly inhibited the elevation of the DNA damage response, apoptosis, and inflammation in H/R-injured renal tubular cells and suppressed adriamycin-induced DNA damage response. Similarly, overexpression of ELA32 or ELA11 significantly inhibited H/R-induced cell death, DNA damage response, and inflammation. Notably, treatment of mice with ELA32 or ELA11 but not an ELA11 mutant with a cysteine to alanine substitution at the N terminus (AE11C) inhibited I/R injury-induced renal fibrosis, inflammation, apoptosis, and the DNA damage response and markedly reduced the renal tubular lesions and renal dysfunction. Together, our results suggest that ELA32 and ELA11 may be therapeutic candidates for treating AKI.
10.1681/ASN.2016111210
Reduced ELABELA expression attenuates trophoblast invasion through the PI3K/AKT/mTOR pathway in early onset preeclampsia.
Wang Lijing,Zhang Yan,Qu Hongmei,Xu Fengsen,Hu Haiyan,Zhang Qian,Ye Yuanhua
Placenta
INTRODUCTION:Early onset preeclampsia is linked to abnormal trophoblast invasion, leading to insufficient recasting of uterine spiral arteries and shallow placental implantation. This study investigated ELABELA (ELA) expression and its involvement in the pathogenesis of early onset preeclampsia. METHODS:We used immunohistochemistry, quantitative PCR and Western blot to calculate ELA levels in the placentas. Transwell assays were utilize to assess the invasion and migration of trophoblastic Cells. Western blot was used to identify the concentrations of vital kinases in PI3K/AKT/mTOR pathways and invasion-related proteins in trophoblast cells. RESULTS:ELA was expressed in villous cytotrophoblasts and syncytiotrophoblasts in placental tissue. Compared with the normal pregnancies, ELA mRNA and protein expression was significantly reduced in early onset preeclampsia placentas. In the HTR-8/SVneo cells, when ELA was knocked down, the invasion and migration capability of cells decreased significantly, with MMP2 and MMP9 expression downregulated and the expression of important kinases in the PI3K/AKT/mTOR pathways being significantly decreased compared to the control group. Overexpression of ELA was on the contrary. Besides, while PI3K was blocked, the invasion and migration capability of HTR-8/SVneo cells and the expression of key kinases in PI3K/AKT/mTOR pathways were decreased significantly. DISCUSSION:ELA stimulates the invasion and migration of trophoblastic cells through activation of downstream PI3K/AKT/mTOR pathway and is complicit in early onset preeclampsia pathogenesis. Our research offers a potential novel treatment for PE.
10.1016/j.placenta.2019.08.077
PEGylated and Acylated Elabela Analogues Show Enhanced Receptor Binding, Prolonged Stability, and Remedy of Acute Kidney Injury.
Wang Chao,Xiong Mingrui,Yang Chen,Yang Dong,Zheng Jiaojiao,Fan Yu,Wang Shun,Gai Yongkang,Lan Xiaoli,Chen Hong,Zheng Ling,Huang Kun
Journal of medicinal chemistry
Acute kidney injury (AKI), mostly caused by renal ischemia-reperfusion (I/R) injury and nephrotoxins, is characterized by rapid deterioration in renal-functions without effective drug treatment available. Through activation of a G protein-coupled receptor APJ, a furin-cleaved fragment of Elabela (ELA[22-32], E11), an endogenous APJ ligand, protects against renal I/R injury. However, the poor plasma stability and relatively weak APJ-binding ability of E11 limit its application. To address these issues, we rationally designed and synthesized a set of E11 analogues modified by palmitic acid (Pal) or polyethylene glycol; improved plasma stability and APJ-binding capacity of these analogues were achieved. In cultured renal tubular cells, these analogues protected against hypoxia-reperfusion or cisplatin-caused injury. For renal I/R-injured mice, these analogues showed improved reno-protective effects than E11; notably, Pal-E11 showed therapeutic effects at 24 h post I/R injury. These results present ELA analogues as potential therapeutic options in managing AKI.
10.1021/acs.jmedchem.0c01913
The Elabela-APJ axis: a promising therapeutic target for heart failure.
Heart failure reviews
Heart failure (HF) is a growing epidemic with high morbidity and mortality at an international scale. The apelin-APJ receptor pathway has been implicated in HF, making it a promising therapeutic target. APJ has been shown to be activated by a novel endogenous peptide ligand known as Elabela (ELA, also called Toddler or Apela), with a critical role in cardiac development and function. Activation of the ELA-APJ receptor axis exerts a wide range of physiological effects, including depressor response, positive inotropic action, diuresis, anti-inflammatory, anti-fibrotic, and anti-remodeling, leading to its cardiovascular protection. The ELA-APJ axis is essential for diverse biological processes and has been shown to regulate fluid homeostasis, myocardial contractility, vasodilation, angiogenesis, cellular differentiation, apoptosis, oxidative stress, cardiorenal fibrosis, and dysfunction. The beneficial effects of the ELA-APJ receptor system are well-established by treating hypertension, myocardial infarction, and HF. Additionally, administration of ELA protects human embryonic stem cells against apoptosis and stress-induced cell death and promotes survival and self-renewal in an APJ-independent manner (X receptor) via the phosphatidylinositol 3-kinase/Akt pathway, which may provide a new therapeutic approach for HF. Thus, targeting the ELA-APJ axis has emerged as a pre-warning biomarker and a novel therapeutic approach against progression of HF. An increased understanding of cardiovascular actions of ELA will help to develop effective interventions. This article gives an overview of the characteristics of the ELA-apelin-APJ axis and summarizes the current knowledge on its cardioprotective roles, potential mechanisms, and prospective application for acute and chronic HF.
10.1007/s10741-020-09957-5
The role of Elabela in kidney disease.
Zheng Qian,Tian Geng,Xu Feng,Ci Xin,Luan Rumei,Wu Linlin,Lu Xuehong
International urology and nephrology
Elabela, also known as Toddler or Apela, is a recently discovered hormonal peptide containing 32 amino acids. Elabela is a ligand of the apelin receptor (APJ). APJ is a G protein-coupled receptor widely expressed throughout body, and together with its cognate ligand, apelin, it plays an important role in various physiological processes including cardiovascular functions, angiogenesis and fluid homeostasis. Elabela also participates in embryonic development and pathophysiological processes in adulthood. Elabela is highly expressed in undifferentiated embryonic stem cells and regulates endoderm differentiation and cardiovascular system development. During differentiation, Elabela is highly expressed in pluripotent stem cells and in adult renal collecting ducts and loops, where it functions to maintain water and sodium homeostasis. Other studies have also shown that Elabela plays a crucial role in the pathogenesis of kidney diseases. This review addresses the role of Elabela in kidney diseases including renal ischemia/reperfusion injury, hypertensive nephropathy, diabetic nephropathy, and cardiorenal syndrome.
10.1007/s11255-021-02790-1
Fc-Elabela fusion protein attenuates lipopolysaccharide-induced kidney injury in mice.
Xu Feng,Zhou Huifen,Wu Man,Zhang Hong,Zhang Yixian,Zhao Qingbin,Brown Robert,Gong Da-Wei,Miao Lining
Bioscience reports
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.
10.1042/BSR20192397
An Apela RNA-Containing Negative Feedback Loop Regulates p53-Mediated Apoptosis in Embryonic Stem Cells.
Li Mangmang,Gou Hongfeng,Tripathi Brajendra K,Huang Jing,Jiang Shunlin,Dubois Wendy,Waybright Tim,Lei Ming,Shi Jianxin,Zhou Ming,Huang Jing
Cell stem cell
Maintaining genomic integrity is of paramount importance to embryonic stem cells (ESCs), as mutations are readily propagated to daughter cells. ESCs display hypersensitivity to DNA damage-induced apoptosis (DIA) to prevent such propagation, although the molecular mechanisms underlying this apoptotic response are unclear. Here, we report that the regulatory RNA Apela positively regulates p53-mediated DIA. Apela is highly expressed in mouse ESCs and is repressed by p53 activation, and Apela depletion compromises p53-dependent DIA. Although Apela contains a coding region, this coding ability is dispensable for Apela's role in p53-mediated DIA. Instead, Apela functions as a regulatory RNA and interacts with hnRNPL, which prevents the mitochondrial localization and activation of p53. Together, these results describe a tri-element negative feedback loop composed of p53, Apela, and hnRNPL that regulates p53-mediated DIA, and they further demonstrate that regulatory RNAs add a layer of complexity to the apoptotic response of ESCs after DNA damage.
10.1016/j.stem.2015.04.002
APELA promotes tumour growth and cell migration in ovarian cancer in a p53-dependent manner.
Yi Yuyin,Tsai Shu-Huei,Cheng Jung-Chien,Wang Evan Y,Anglesio Michael S,Cochrane Dawn R,Fuller Megan,Gibb Ewan A,Wei Wei,Huntsman David G,Karsan Aly,Hoodless Pamela A
Gynecologic oncology
OBJECTIVE:APELA is a small, secreted peptide that can function as a ligand for the G-protein coupled receptor, Apelin Receptor (APLNR, APJ). APELA plays an essential role in endoderm differentiation and cardiac development during embryogenesis. We investigated whether APELA exerts any functions in cancer progression. METHODS:The Cancer Genome Atlas (TCGA) RNA sequencing datasets, microarray from an OCCC mouse model, and RNA isolated from fresh frozen and FFPE patient tissue were used to assess APELA expression. APELA knockout ovarian clear cell carcinoma (OCCC) cell lines were generated using CRISPR/Cas9. RESULTS:APELA was expressed in various ovarian cancer histotypes and was especially elevated in OCCC. Disruption of APELA expression in OCCC cell lines suppressed cell growth and migration, and altered cell-cycle progression. Moreover, addition of human recombinant APELA peptide to the OCCC cell line OVISE promoted cell growth and migration. Interestingly, OVISE cells do not express APLNR, suggesting that APELA can function through an APLNR-independent pathway. Furthermore, APELA affected cell growth and cell cycle progression in a p53-dependent manner. In addition, APELA knockdown induced p53 expression in cancer cell lines. CONCLUSIONS:Our findings uncover a potential oncogenic role for APELA in promoting ovarian tumour progression and provide a possible therapeutic strategy in ovarian cancer by targeting APELA.
10.1016/j.ygyno.2017.10.016
Characterization of apela, a novel endogenous ligand of apelin receptor, in the adult heart.
Perjés Ábel,Kilpiö Teemu,Ulvila Johanna,Magga Johanna,Alakoski Tarja,Szabó Zoltán,Vainio Laura,Halmetoja Eveliina,Vuolteenaho Olli,Petäjä-Repo Ulla,Szokodi István,Kerkelä Risto
Basic research in cardiology
The G protein-coupled apelin receptor regulates important processes of the cardiovascular homeostasis, including cardiac development, cardiac contractility, and vascular tone. Most recently, a novel endogenous peptide ligand for the apelin receptor was identified in zebrafish, and it was named apela/elabela/toddler. The peptide was originally considered as an exclusively embryonic regulator, and so far its function in the adult organism remains elusive. We show here that apela is predominantly expressed in the non-cardiomyocyte fraction in the adult rodent heart. We also provide evidence that apela binds to apelin receptors in the heart. Using isolated adult rat hearts, we demonstrate, that just like the fellow receptor agonist apelin, apela increases cardiac contractility and induces coronary vasodilation already in the nanomolar level. The inotropic effect, as revealed by Western blot analysis, is accompanied by a significant increase in extracellular signal-regulated kinase (ERK) 1/2 phosphorylation. Pharmacological inhibition of ERK1/2 activation markedly attenuates the apela-induced inotropy. Analysis of samples from infarcted mouse hearts showed that expression of both apela and apelin receptor is induced in failing mouse hearts and correlate with left ventricular ejection fraction. Hence, we conclude that apela is present in the adult heart, is upregulated in post-infarction cardiac remodeling, and increases cardiac contractility in an ERK1/2-dependent manner.
10.1007/s00395-015-0521-6
ELABELA antagonizes intrarenal renin-angiotensin system to lower blood pressure and protects against renal injury.
Xu Chuanming,Wang Fei,Chen Yanting,Xie Shiying,Sng Danielle,Reversade Bruno,Yang Tianxin
American journal of physiology. Renal physiology
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 and 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·day, 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 (, , , , , , , and ), fibrosis markers (, , , , and ), and kidney injury markers (, , albuminuria, and urinary 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.
10.1152/ajprenal.00606.2019
ELABELA Is an Endogenous Growth Factor that Sustains hESC Self-Renewal via the PI3K/AKT Pathway.
Ho Lena,Tan Shawn Y X,Wee Sheena,Wu Yixuan,Tan Sam J C,Ramakrishna Navin B,Chng Serene C,Nama Srikanth,Szczerbinska Iwona,Sczerbinska Iwona,Chan Yun-Shen,Avery Stuart,Tsuneyoshi Norihiro,Ng Huck Hui,Gunaratne Jayantha,Dunn N Ray,Reversade Bruno
Cell stem cell
ELABELA (ELA) is a peptide hormone required for heart development that signals via the Apelin Receptor (APLNR, APJ). ELA is also abundantly secreted by human embryonic stem cells (hESCs), which do not express APLNR. Here we show that ELA signals in a paracrine fashion in hESCs to maintain self-renewal. ELA inhibition by CRISPR/Cas9-mediated deletion, shRNA, or neutralizing antibodies causes reduced hESC growth, cell death, and loss of pluripotency. Global phosphoproteomic and transcriptomic analyses of ELA-pulsed hESCs show that it activates PI3K/AKT/mTORC1 signaling required for cell survival. ELA promotes hESC cell-cycle progression and protein translation and blocks stress-induced apoptosis. INSULIN and ELA have partially overlapping functions in hESC medium, but only ELA can potentiate the TGFβ pathway to prime hESCs toward the endoderm lineage. We propose that ELA, acting through an alternate cell-surface receptor, is an endogenous secreted growth factor in human embryos and hESCs that promotes growth and pluripotency.
10.1016/j.stem.2015.08.010
[The functional role of endogenous APJ agonists; Apelin and Elabela/Toddler in cardiovascular diseases].
Sato Teruki,Kuba Keiji
Nihon yakurigaku zasshi. Folia pharmacologica Japonica
Apelin is an endogenous peptide ligand for APJ receptor, which is widely expressed in human body, and exerts various physiological effects such as vasodilation, inotropic effect, water balance, heart development, angiogenesis and energy metabolism. The beneficial effects of Apelin in cardiovascular diseases have been elucidated, and the roles of Apelin in aging-associated diseases are recently implicated. The mechanisms for therapeutic effects of Aplein include an antagonistic action to renin-angiotensin system (RAS) in addition to inotropic and vasodilatory actions. We have revealed that endogenous Apelin negatively regulates RAS via upregulation of Angiotensin converting enzyme 2 (ACE2). In addition, a second ligand for APJ receptor, Elabela/Toddler, was identified as an essential hormone for heart development, and it has been reported to have physiological effects similar to Apelin. We and others have shown that Elabela exerts inotropic and protective effects in the heart. Although the number of heart failure patients is rapidly increasing, the pathophysiology of heart failure remains elusive and further development of new therapeutic option is awaited. Apelin is a unique bifunctional molecule, which has both inotropic and cardioprotective effects in heart failure, and thus further elucidation of the mechanisms for Apelin/Elabela-APJ signaling would contribute to development of a novel therapeutics for heart failure patients.
10.1254/fpj.153.172
Elabela protects against podocyte injury in mice with streptozocin-induced diabetes by associating with the PI3K/Akt/mTOR pathway.
Zhang Yixian,Wang Yangwei,Luo Manyu,Xu Feng,Lu Yue,Zhou Xiaoxi,Cui Wenpeng,Miao Lining
Peptides
Diabetic nephropathy is a common complication of diabetes characterized by an increased rate of protein excretion in urine and kidney function loss. Elabela is a newly discovered peptide whose role in the regulation of diabetes is the major focus of this research. We established an in vivo model of Type 1 diabetes mellitus by injecting mice intraperitoneally with streptozotocin. The treatment group was administered Elabela for 6 months. In the present study, Elabela administration under diabetic conditions was found to reduce renal inflammation and fibrosis markers, leading to improvement in renal pathology and kidney dysfunction. Furthermore, Elabela acts through the phosphoinositide 3-kinase /Akt/mammalian target of rapamycin signaling pathway and decreases podocyte apoptosis, thereby exhibiting a nephroprotective effect against diabetic nephropathy. Our findings provide the first evidence that Elabela has a potential renoprotective effect in patients of diabetes.
10.1016/j.peptides.2019.04.005
The Effects of Apelin and Elabela Ligands on Apelin Receptor Distinct Signaling Profiles.
Jiang Yunlu,Yan Maocai,Wang Chunmei,Wang Qinqin,Chen Xiaoyu,Zhang Rumin,Wan Lei,Ji Bingyuan,Dong Bo,Wang Huiyun,Chen Jing
Frontiers in pharmacology
Apelin and Elabela are endogenous peptide ligands for Apelin receptor (APJ), a widely expressed G protein-coupled receptor. They constitute a spatiotemporal dual ligand system to control APJ signal transduction and function. We investigated the effects of Apelin-13, pGlu-apelin-13, Apelin-17, Apelin-36, Elabela-21 and Elabela-32 peptides on APJ signal transduction. Whether different ligands are biased to different APJ mediated signal transduction pathways was studied. We observed the different changes of G protein dependent and β-arrestin dependent signaling pathways after APJ was activated by six peptide ligands. We demonstrated that stimulation with APJ ligands resulted in dose-dependent increases in both G protein dependent [cyclic AMP (cAMP), Ca mobilization, and the early phase extracellular related kinase (ERK) activation] and β-arrestin dependent [GRKs, β-arrestin 1, β-arrestin 2, and β2 subunit of the clathrin adaptor AP2] signaling pathways. However, the ligands exhibited distinct signaling profiles. Elabela-32 showed a >1000-fold bias to the β-statin-dependent signaling pathway. These data provide that Apelin-17 was biased toward β-arrestin dependent signaling. Eabela-21 and pGlu-Apelin-13 exhibited very distinct activities on the G protein dependent pathway. The activity profiles of these ligands could be valuable for the development of drugs with high selectivity for specific APJ downstream signaling pathways.
10.3389/fphar.2021.630548
Elabela alleviates myocardial ischemia reperfusion-induced apoptosis, fibrosis and mitochondrial dysfunction through PI3K/AKT signaling.
Yu Peng,Ma Sicong,Dai Xinchun,Cao Feng
American journal of translational research
Myocardial ischemia/reperfusion (I/R) injury is a common cardiovascular disease with high morbidity and mortality globally, which derives from acute myocardial infarction and coronary artery disease. Elabela has been proved to bind to apelin receptors in the heart. The present study aimed to investigate the protective effects of Elabela in myocardial I/R injury and illustrating the potential mechanisms. In this study, the rat I/R model was established . Following treatment with Elabela, the histopathological changes of heart tissue were evaluated by the hematoxylin and eosin- or Masson's trichrome staining. Apoptosis of heart tissue was examined using TUNEL staining. The expression of type I or III collagen and apoptosis-associated proteins was measured using western blotting. Moreover, myocardial ultrastructure in myocardium was detected via electron microscopy analysis. H9c2 cells were treated with hypoxia/reoxygenation (H/R) to mimic the myocardial I/R injury . After treatment with Elabela or Elabela combined with LY294002, the levels of oxidative stress and apoptosis were examined. The results revealed that Elabela significantly improved the pathological changes of rat myocardial tissues induced by I/R. Additionally, Elabela treatment reduced cardiomyocyte I/R induced fibrosis and apoptosis as well as ameliorated mitochondrial dysfunction in animal and cells. Within inhibition of PI3K pathway, the protective effects of Elabela was reversed. Taken together, these findings demonstrated that Elabela could protect against fibrosis, apoptosis and oxidative stress via PI3K/ATK signaling pathway in cardiac ischemia reperfusion.