Affinage

APLNR

Apelin receptor · UniProt P35414

Audit flag: ungrounded claim
Length
380 aa
Mass
42.7 kDa
Annotated
2026-06-09
100 papers in source corpus 29 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

APLNR (APJ) is a class A G-protein-coupled receptor that integrates peptide-ligand and mechanical inputs to control vascular, cardiac, metabolic, and reproductive physiology (PMID:22810587, PMID:12603839). Its endogenous apelin peptides bind the human receptor with potency dictated by defined residues of apelin-13 (PMID:12603839), coupling APJ predominantly to pertussis-toxin-sensitive Gαi to activate PI3K→Akt and FAK signaling that drives focal adhesion formation, actin reorganization, and cell motility (PMID:16211245); the second peptide ligand Elabela engages APJ to activate Gα13-dependent NRF2/ARE antioxidative signaling and YAP/TAZ-dependent angiogenesis (PMID:36681202, PMID:36813109). APJ is bifunctional: apelin/Gαi signaling is cardioprotective, whereas mechanical stretch or static pressure signals through APJ in a G-protein-independent, β-arrestin-dependent manner to drive cardiomyocyte hypertrophy (PMID:22810587, PMID:24966188). Ligand binding triggers rapid clathrin-mediated internalization that requires the intact cytoplasmic C-terminal domain, with apelin-13-bound receptor recycling to the surface (PMID:12667811). In the endothelium APJ acts downstream of the ERG transcription factor to maintain venular homeostasis (PMID:25062690) and orchestrates a miR-139-5p→CXCR4 axis controlling developmental vascular patterning (PMID:27068353) and a FOXO1→FABP4 axis governing endothelial fatty-acid handling and systemic glucose utilization (PMID:28904225). APJ further modulates receptor crosstalk, constitutively suppressing AngII/AT1-mediated ERK1/2 signaling in the ligand-free state and relieving this suppression upon apelin binding (PMID:21412239), and forming a functional heterodimer with the bradykinin B2 receptor that drives PLC/ERK1/2/eNOS-dependent endothelial proliferation (PMID:32407761). In disease, APJ hyperactivation by locally produced apelin suppresses carnitine production and adhesion gene expression in Sertoli cells to disrupt the blood-testis barrier in diabetes (PMID:36443325), and APJ drives pro-metastatic and pro-invasive programs in ovarian cancer and glioblastoma via STAT3, ERK, and AKT signaling (PMID:30358318, PMID:30858172).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2000 High

    Established that APJ is a functional cell-surface receptor with biological activity beyond an orphan GPCR by showing it serves as a primate immunodeficiency virus coreceptor blockable by its peptide ligand.

    Evidence Cell-cell fusion and coreceptor assays with apelin-13 blockade and Western blot glycosylation analysis

    PMID:11040134

    Open questions at the time
    • Does not define physiological signaling output
    • Coreceptor role distinct from native ligand signaling
  2. 2003 High

    Defined the molecular determinants of apelin binding to human APJ, establishing the ligand pharmacophore.

    Evidence Radioligand binding and functional assays with systematic apelin-13 analogue mutagenesis at recombinant human APJ

    PMID:12603839

    Open questions at the time
    • No receptor structural model
    • Downstream signaling not resolved in this study
  3. 2003 High

    Answered how APJ signaling is terminated and reset by demonstrating C-terminal-dependent clathrin-mediated internalization and ligand-specific recycling.

    Evidence APJ-GFP live-cell imaging, fluorescent apelin, transferrin receptor co-localization, and C-terminal truncation mutants

    PMID:12667811

    Open questions at the time
    • Specific C-terminal motifs/phosphosites not mapped
    • Arrestin involvement in internalization not directly tested
  4. 2005 High

    Identified the proximal G-protein-coupled signaling cascade, linking APJ to Gi-PI3K/Akt-FAK and cell motility.

    Evidence Stable APJ-HEK293T cells with pertussis toxin, PI3K inhibitor, phospho-immunoblotting, and migration assays

    PMID:16211245

    Open questions at the time
    • Cell-type generality untested
    • Does not address mechanical/biased signaling
  5. 2011 Medium

    Revealed that ligand-free APJ has constitutive activity by suppressing AT1/AngII ERK1/2 signaling that apelin binding relieves.

    Evidence HEK293 APJ/AT1 co-expression, pertussis toxin, receptor controls, ERK1/2 immunoblotting

    PMID:21412239

    Open questions at the time
    • Single ERK1/2 readout from one lab
    • Physiological/in vivo relevance untested
  6. 2012 High

    Defined APJ as a bifunctional receptor distinguishing protective apelin/Gαi signaling from pathological stretch-induced β-arrestin-dependent hypertrophy.

    Evidence APJ-null and apelin-null mice, isolated cardiomyocyte stretch assay, β-arrestin knockdown, Gαi pharmacology

    PMID:22810587

    Open questions at the time
    • Structural basis of biased mechanosensing unknown
    • Arrestin effector identity in hypertrophy unresolved
  7. 2012 Medium

    Showed APJ functions as an apelin chemoattractant receptor on circulating progenitor cells supporting myocardial repair.

    Evidence Bone marrow Aplnr knockdown, apelin injection into ischemic myocardium, flow cytometry, cardiac function readouts

    PMID:22753078

    Open questions at the time
    • Single lab
    • Paracrine effectors not identified
  8. 2014 High

    Placed APLNR in a transcriptional hierarchy by identifying ERG as a direct activator required for venular endothelial homeostasis.

    Evidence Erg/Aplnr knockout mice, endothelium-specific deletion, ChIP/promoter binding, human lung tissue

    PMID:25062690

    Open questions at the time
    • Downstream effectors of APLNR in venular ECs not fully defined here
    • Ligand dependence of phenotype unclear
  9. 2014 Medium

    Extended the mechanosensor role to static pressure, linking APJ to PI3K/Akt/autophagy-driven cardiomyocyte hypertrophy.

    Evidence Rat hypertrophy model, H9c2 static pressure culture, APJ shRNA, PI3K/Akt/autophagy inhibitors

    PMID:24966188

    Open questions at the time
    • No rescue experiments
    • Relationship to β-arrestin stretch pathway not reconciled
  10. 2015 Medium

    Identified a HIF-1α→apelin/APJ→autophagy axis driving hypoxia-induced proliferation in stem and progenitor cells.

    Evidence BMSC and EPC hypoxia cultures, sequential siRNA knockdown of HIF-1α/APJ/Beclin-1, MAPK inhibitors, proliferation assays

    PMID:25736405 PMID:26676468

    Open questions at the time
    • Single lab per cell type
    • Direct receptor-effector coupling not biochemically resolved
  11. 2016 High

    Defined an endothelial APJ→miR-139-5p→CXCR4 axis controlling vascular patterning, induced by laminar flow.

    Evidence Apln/Aplnr global and endothelial-specific knockouts, retinal phenotyping, miR-139-5p inhibition, CXCR4 blockade

    PMID:27068353

    Open questions at the time
    • Mechanism of miR-139-5p induction by APJ unresolved
    • Flow-sensing versus ligand contribution not separated
  12. 2016 Medium

    Connected APJ to ligand-independent shear-stress responses and NO/proliferation signaling in endothelium.

    Evidence siRNA knockdown in human ECs, shear-stress flow chamber, NO measurement, PI3K/Akt/ERK1/2 immunoblotting

    PMID:25817266

    Open questions at the time
    • Single lab
    • Mechanism of shear-induced APJ upregulation unknown
  13. 2017 High

    Established APJ as a regulator of systemic metabolism through an endothelial FOXO1→FABP4 fatty-acid handling axis.

    Evidence Endothelial-specific Aplnr knockout, Foxo1 epistasis, FABP4 inhibition, glucose utilization assays

    PMID:28904225

    Open questions at the time
    • Direct biochemical link from APJ to FOXO1 inactivation not mapped
    • G-protein dependence not dissected
  14. 2019 Medium

    Demonstrated APJ drives pro-metastatic and invasive tumor programs via STAT3/ERK/AKT in ovarian cancer and glioblastoma.

    Evidence Gain/loss-of-function in tumor cells, in vivo metastasis/invasion models, ML221 and apelin-F13A antagonists, VEGFR2 cotargeting

    PMID:30358318 PMID:30858172

    Open questions at the time
    • Single lab per tumor type
    • Context-dependent tumor-suppressive role elsewhere unexplained
  15. 2020 Medium

    Showed APJ engages in receptor crosstalk by heterodimerizing with the bradykinin B2 receptor to drive eNOS-dependent endothelial proliferation.

    Evidence BRET, FRET, proximity ligation, co-IP in HUVECs/HEK293, siRNA knockdown, ERK1/2/eNOS phosphorylation

    PMID:32407761

    Open questions at the time
    • Stoichiometry and structural interface unknown
    • In vivo relevance of heterodimer untested
  16. 2022 High

    Defined a pathological APJ hyperactivation mechanism disrupting the blood-testis barrier in diabetes via carnitine and adhesion suppression.

    Evidence scRNA-seq of diabetic testes, high-glucose Sertoli cell treatment, ML221 rescue in db/db mice and human testis culture

    PMID:36443325

    Open questions at the time
    • Signaling node linking APJ to carnitine repression unmapped
    • Receptor coupling (G-protein vs arrestin) not defined
  17. 2023 Medium

    Established Elabela as a second APJ ligand engaging distinct Gα13/NRF2 and YAP/TAZ pathways in protective cytoprotection and angiogenesis.

    Evidence ELA-32 treatment in cerebral and renal I/R models, AAV/siRNA APJ knockdown, NRF2 and YAP inhibitors, RNA-seq

    PMID:36681202 PMID:36813109 PMID:37351176

    Open questions at the time
    • Ligand bias between apelin and Elabela not structurally defined
    • Single lab per organ system

Open questions

Synthesis pass · forward-looking unresolved questions
  • How APJ structurally encodes biased signaling among Gαi, Gα13, β-arrestin, and mechanical inputs, and how distinct ligands and heterodimers select these outputs, remains unresolved.
  • No receptor structure or biased-agonism model in the corpus
  • Mechanism of mechanosensing unknown
  • Determinants of apelin vs Elabela pathway selection undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0001618 virus receptor activity 1 GO:0048018 receptor ligand activity 1 GO:0120274 virus coreceptor activity 1
Localization
GO:0005886 plasma membrane 3 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-1430728 Metabolism 2 R-HSA-9612973 Autophagy 2
Partners
AGTR1APELAAPLNBDKRB2
Complex memberships
APJ-B2R heterodimer

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 APJ acts as a dual-function receptor: apelin stimulation couples APJ to Gαi signaling and elicits a cardioprotective response, whereas mechanical stretch signals through APJ in a G-protein-independent, β-arrestin-dependent manner to induce cardiomyocyte hypertrophy. Knockdown of β-arrestins blocked stretch-mediated hypertrophy, and pharmacological doses of apelin acting through Gαi prevented it. Genetic loss-of-function (APJ-null and apelin-null mice), freshly isolated cardiomyocyte stretch assay, β-arrestin knockdown, Gαi pharmacology, cardiomyocyte size measurement Nature High 22810587
2014 ERG is a transcriptional activator of the APLNR gene and binds to the Aplnr promoter. Knockout of either Erg or Aplnr causes pulmonary venule-specific endothelial proliferation in vitro and pulmonary veno-occlusive disease in vivo, placing APLNR downstream of ERG in a pathway essential for venular endothelial homeostasis. Erg/Aplnr knockout mice, endothelium-directed conditional Aplnr deletion, in vitro proliferation assays, ChIP/transcriptional activation studies, patient lung tissue analysis Circulation High 25062690
2016 APLNR-mediated APLN/APLNR signaling in endothelial cells induces transcription of miR-139-5p (promoted by laminar flow), which in turn suppresses endothelial CXCR4 expression. Loss of Apln, Aplnr, or endothelial-specific Aplnr caused dysregulated CXCR4 upregulation and retinal vascular defects; pharmacological inhibition of CXCR4 or augmentation of the miR-139-5p axis rescued these defects. Apln/Aplnr global and endothelial-specific knockout mice, retinal vascular phenotyping, miR-139-5p in vivo inhibition, pharmacological CXCR4 blockade Nature communications High 27068353
2017 Endothelial APLNR signaling inactivates FOXO1 and suppresses endothelial expression of fatty acid binding protein 4 (FABP4). Conditional endothelial-specific Aplnr deletion impaired glucose utilization and abrogated apelin-induced glucose lowering; excess tissue fatty acid accumulation in skeletal muscle was the mechanistic link. Concurrent endothelial Foxo1 deletion or pharmacologic FABP4 inhibition rescued the metabolic phenotype. Endothelial-specific conditional Aplnr knockout mice, FOXO1 knockout epistasis, pharmacological FABP4 inhibition, metabolic and glucose utilization assays Science translational medicine High 28904225
2003 Apelin peptides are endogenous ligands for the human APJ (APLNR) receptor. Structure-activity studies identified that leucine at position 5 and arginine at positions 2 and 4 of apelin-13 are key residues required for functional potency and binding affinity at the recombinant human APJ receptor. Radioligand binding assays, functional assays with apelin analogues at human recombinant APJ receptor, quantitative RT-PCR, immunohistochemistry Journal of neurochemistry High 12603839
2003 APJ receptor undergoes rapid, dose-dependent ligand-induced internalization upon stimulation with Apelin-36 and Apelin-13 via clathrin-coated pits (co-localization with transferrin receptor). The intact cytoplasmic C-terminal domain of APJ is required for ligand-induced internalization. Internalized APJ recycled to the cell surface within 60 min after Apelin-13 removal, but most internalized receptor remained in the cytoplasm 2 h after Apelin-36 washout. APJ-GFP stable expression, fluorescent apelin peptide (5-CF-Apelin-13), co-localization with transferrin receptor, C-terminal truncation mutants, live cell imaging Virology High 12667811
2005 Apelin/APJ signaling via a pertussis toxin-sensitive Gi protein activates PI3K→Akt/PKB and focal adhesion kinase (FAK) phosphorylation, increases focal adhesion formation with actin reorganization, and stimulates cell motility in APJ-expressing cells. Stable APJ-expressing HEK293T cells, radioligand binding, pertussis toxin treatment, PI3K inhibitor (LY294002), phospho-Akt/FAK immunoblotting, scratch migration assay, F-actin staining International journal of molecular medicine High 16211245
2000 APJ functions as a coreceptor for primate immunodeficiency viruses (HIV-1 and SIV). APJ coreceptor activity is demonstrable even at low expression levels, and the endogenous peptide ligand apelin-13 efficiently blocked APJ coreceptor activity. APJ is N-glycosylated as determined by Western blot with a specific monoclonal antibody. Monoclonal antibody (MAb 856) production, FACS, Western blot, immunofluorescence, cell-cell fusion assays, apelin-13 blockade of coreceptor activity Virology High 11040134
2011 Non-activated (ligand-free) APJ suppresses angiotensin II (AngII)/AT1-mediated ERK1/2 phosphorylation in a receptor-proximity-dependent manner independent of heterodimerization, whereas apelin-activated APJ reverses this suppression through Gαi (pertussis toxin-sensitive). Thus APJ has a constitutive, ligand-independent inhibitory interaction with AT1 signaling that is abolished upon apelin binding. HEK293 cell co-expression of APJ and AT1, pertussis toxin treatment, AT2 and β2-adrenergic receptor controls, ERK1/2 phosphorylation immunoblotting, AT1 blocker dose-response Hypertension research Medium 21412239
2016 Apelin/APLNR signaling promotes endothelial cell (EC) proliferation via PI3K/Akt-mediated activation, and apelin-12 activates NO production via the PI3K/Akt pathway in human ECs. Apelin-13 additionally activates Erk1/2 phosphorylation and enhances EC proliferation. APJ knockdown inhibited PI3K phosphorylation and impaired flow-induced eNOS and PECAM-1 expression; APJ expression is induced by shear stress independently of its ligand. siRNA knockdown of APJ or apelin in human ECs, shear stress flow chamber, NO measurement, PI3K/Akt and ERK1/2 phosphorylation immunoblotting, gene and protein expression under flow Cellular signalling Medium 25817266
2014 APJ receptor acts as a static pressure sensor in cardiomyocytes. Static pressure upregulates APJ expression and activates PI3K/Akt/autophagy (LC3-II/I, Beclin-1) signaling to promote cardiomyocyte hypertrophy. APJ shRNA, PI3K inhibitor (LY294002), Akt inhibitor, and autophagy inhibitor (3-methyladenine) each reversed pressure-induced increases in cell diameter, volume, and protein content. Rat left ventricular hypertrophy model (aortic coarctation), H9c2 cardiomyocyte static pressure culture, APJ shRNA knockdown, PI3K/Akt inhibitors, LC3/Beclin-1 immunoblotting, cell size measurements Acta biochimica et biophysica Sinica Medium 24966188
2015 Hypoxia-induced HIF-1α upregulates apelin and APLNR expression in bone marrow-derived mesenchymal stem cells (BMSCs), and this apelin/APJ/autophagy axis mediates hypoxia-induced BMSC proliferation. siRNA-HIF-1α suppressed apelin, APJ, Beclin-1, and LC3II/LC3I; siRNA-APJ suppressed Beclin-1 and LC3II/LC3I and reversed proliferation; siRNA-Beclin-1 abolished proliferation. Mouse BMSC hypoxia culture, siRNA knockdown of HIF-1α/APJ/Beclin-1, MTT and BrdU proliferation assays, Western blot for autophagy markers Acta biochimica et biophysica Sinica Medium 25736405
2015 Hypoxia upregulates HIF-1α, Apelin, and APLNR in endothelial progenitor cells (EPCs), and the Apelin/APLNR axis mediates hypoxia-induced EPC proliferation via downstream MAPK signaling. siRNA knockdown of Apelin or APLNR suppressed hypoxia-induced proliferation; MAPK inhibitors (SB-239063 and PD98059) eliminated Apelin upregulation-induced EPC proliferation. Human EPC hypoxia culture, siRNA knockdown of Apelin/APLNR, MAPK inhibitors, MTT proliferation assay, RT-qPCR and Western blot Molecular medicine reports Medium 26676468
2012 APLNR (Aplnr) is specifically expressed on circulating cKit+/Flk1+ cells and functions as a receptor for apelin-mediated chemoattraction during myocardial repair. Apelin injection into ischemic myocardium increased recruitment of cKit+/Flk1+/Aplnr+ cells; Aplnr knockdown in bone marrow aggravated ischemic damage and could not be rescued by apelin. Recruited cells promoted neovascularization via paracrine rather than transdifferentiation mechanisms. Bone marrow Aplnr knockdown, apelin injection into ischemic myocardium, flow cytometry for circulating progenitor populations, scar formation and cardiac function measurement Circulation research Medium 22753078
2016 APLN (apelin) acts through APLNR to increase steroidogenesis in human luteinized granulosa cells (hGCs), enhancing both basal and IGF1-induced steroid secretion by increasing HSD3B protein concentration through activation of the MAPK3/1 (ERK1/2) and AKT pathways. The APLNR antagonist ML221 reversed these effects. IGF1 increased APLNR expression in hGCs. Cultured human luteinized granulosa cells, recombinant apelin-13 and apelin-17 treatment, ML221 APLNR antagonist, pharmacological inhibitors of AKT and MAPK3/1 pathways, Western blot, steroid assays Biology of reproduction Medium 27683264
2022 In Sertoli cells, high glucose induces local APLN production, which via APJ hyperactivation suppresses carnitine production and represses cell adhesion gene expression, leading to blood-testis barrier (BTB) structural dysfunction and impaired spermatogenesis in diabetic models. Pharmacological blockade of APJ with ML221 ameliorated BTB damage and improved spermatogenesis in diabetic db/db mice and cultured human testes. Single-cell RNA sequencing of diabetic patient testes (STRT-seq), high glucose treatment of Sertoli cells, APJ antagonist (ML221) treatment in db/db mice and human testis culture, BTB structural assessment Nature communications High 36443325
2019 In glioblastoma, APLNR on tumor cells mediates apelin-induced migration and invasion. Apelin reduction led to accelerated tumor cell invasion by APLNR-positive cells. Mutant APLNR ligand apelin-F13A blocked both tumor angiogenesis and GBM cell invasion, and cotargeting VEGFR2 and APLNR synergistically improved survival in proneural GBM mouse models. APLN knockdown/knockout in orthotopic GBM models, apelin-F13A peptide treatment, VEGFR2 + APLNR cotargeting, stereotactic biopsy analysis, in vitro and in vivo invasion assays Cancer research Medium 30358318
2019 APJ expression in ovarian cancer cells is necessary and sufficient for pro-metastatic phenotypes (proliferation, adhesion, anoikis resistance, migration, invasion) via downstream activation of STAT3, ERK, and AKT pathways. APJ inhibitor ML221 efficiently inhibited these phenotypes in vitro, and APJ overexpression increased metastasis in vivo. APJ overexpression and knockdown in ovarian cancer cell lines, in vitro adhesion/migration/invasion assays, anoikis assay, in vivo metastasis model, STAT3/ERK/AKT phosphorylation immunoblotting, ML221 inhibitor treatment Molecular cancer research Medium 30858172
2020 APJ and bradykinin B2 receptor (B2R) form a functional heterodimer at the cell membrane, demonstrated by BRET, FRET, proximity ligation assay, and co-immunoprecipitation in HUVECs and transfected cells. Stimulation with apelin-13 and bradykinin increased eNOS phosphorylation via the APJ-B2R heterodimer through a PLC/ERK1/2/eNOS signaling pathway, leading to increased cell proliferation. Silencing of either APJ or B2R inhibited eNOS phosphorylation. BRET and FRET resonance energy transfer, proximity ligation assay, co-immunoprecipitation in HUVECs and HEK293 cells, siRNA knockdown of APJ or B2R, ERK1/2 and eNOS phosphorylation assays, cell proliferation assay Cellular signalling Medium 32407761
2023 ELA (Elabela) binds to APJ and activates the NRF2/ARE antioxidative signaling pathway via Gα13, thereby reducing neuronal ferroptosis after cerebral ischemia/reperfusion injury. AAV-mediated APJ knockdown or the NRF2 inhibitor ML385 abolished the protective effects of ELA-32. ELA-32 peptide treatment in cerebral I/R mouse model, AAV-APJ-RNAi knockdown, NRF2 inhibitor ML385, iron deposition, lipid peroxidation, mitochondrial morphology assays, behavioral readouts Free radical biology & medicine Medium 36681202
2023 ELA (Elabela) binds to APJ in renal tubular cells to regulate renal microvascular blood flow through two downstream mediators: arginine metabolizing enzyme ARG2 and PGE2 metabolizing enzymes CBR1/3. APJ inhibitor ML221 blocked the beneficial effects of exogenous ELA-32 on AKI, while combination treatment with ARG2 inhibitor nor-NOHA and PGE2 activator Paricalcitol alleviated injury independently of APJ, placing ARG2 and CBR1/3 downstream of the ELA-APJ axis. Renal tubule-specific Apela (ELA) knockout mice, bilateral/unilateral I/R models, RNA sequencing, ML221 APJ inhibitor, ARG2 inhibitor (nor-NOHA) and Paricalcitol combination treatment, renal blood flow and functional measurements Theranostics Medium 37351176
1999 The murine msr/apj receptor (ortholog of human APJ/APLNR) is expressed in endothelium of primary blood vessels and the forming heart, as well as in somites, limb bud, and branchial arches during embryonic development, indicating a role in endothelial/vascular lineage specification distinct from Flk1. Molecular cloning, in situ hybridization in developing mouse embryo, comparative expression with Flk1 Mechanisms of development Medium 10473142
2003 APLNR (APJ receptor) mRNA is upregulated in the hypothalamic parvocellular paraventricular nucleus (pPVN) by acute and repeated restraint stress, and adrenalectomy also increased APJR mRNA in the PVN. Adrenalectomized rats showed no further increase above baseline after stress, indicating glucocorticoids negatively regulate APJR mRNA expression and mediate stress-induced regulation. In situ hybridization for APJR mRNA in rat hypothalamus, restraint stress paradigms, adrenalectomy, dual-label in situ hybridization to co-localize APJR and vasopressin mRNA Journal of neuroendocrinology Medium 14622440
2003 APLNR (APJR) mRNA is co-expressed with vasopressin in magnocellular neurons of the hypothalamic PVN and SON, and its expression is induced by osmotic stimuli (2% NaCl loading and water deprivation). Salt-loading increased co-localization of APJR and vasopressin mRNAs in the SON, supporting a role for APJ in the autocrine/paracrine regulation of vasopressin-containing neurons and fluid homeostasis. In situ hybridization histochemistry for APJR mRNA, dual-label in situ hybridization for APJR and vasopressin in salt-loaded and water-deprived rats Journal of neuroendocrinology Medium 12787050
2017 APJ activation by apelin improves AngII-induced endothelial cell senescence via the AMPK/SIRT1 signaling pathway. APJ, AMPK, or SIRT1 knockdown each attenuated the protective effects of apelin. Apelin reduced AngII-induced ROS generation and enhanced telomerase activity in HUVECs. AngII-induced HUVEC senescence model, SA-β-Gal assay, siRNA knockdown of APJ/AMPK/SIRT1, ROS detection, telomerase activity (RQ-TRAP), CCK-8 viability assay, Western blot for P21 and PAI-1 Archives of medical science Low 30002688
2019 APLNR overexpression in nasopharyngeal carcinoma (NPC) cells inhibited migration, invasion, and EMT. Low APLNR expression activated the PI3K-AKT-mTOR signaling pathway to promote EMT. ATRA treatment upregulated APLNR in NPC cell lines and inhibited proliferation; knockdown of APLNR diminished ATRA-induced growth inhibition. APLNR overexpression and knockdown in NPC cell lines, wound-healing and Transwell migration/invasion assays, Western blot for EMT markers and PI3K-AKT-mTOR pathway components, ATRA treatment, cell cycle analysis FASEB journal Medium 31408612
2021 Adipocyte-derived apelin activates APJ on ovarian cancer cells in a paracrine manner, promoting lipid uptake via CD36 upregulation through APJ-STAT3 activation, and the accumulated lipids are utilized for fatty acid oxidation via AMPK-CPT1a axis. APJ antagonist F13A or APJ knockdown reversed lipid accumulation, migration, invasion, and omental homing in vivo. Co-culture with 3T3-L1 adipocyte conditioned media, APJ antagonist F13A, APJ knockdown, in vitro migration/invasion assays, ex vivo omentum adhesion, in vivo homing assay, CD36 and STAT3 pathway analysis, lipid droplet staining Molecular cancer research Medium 34172534
2021 APLNR abrogates the stimulatory effects of 17β-estradiol on OVCAR-3 epithelial ovarian cancer cell proliferation and of IGF-1 on COV434 granulosa cancer cell proliferation via crosstalk between APLNR and estrogen receptor alpha (ERα) or IGF-1 receptor (IGF1R), respectively, independently of ERK1/2 and PI3K pathways. OVCAR-3 and COV434 cell proliferation assays, apelin treatment, ERK1/2 and PI3K pathway inhibitors, estrogen and IGF-1 stimulation, APLNR-ERα/IGF1R crosstalk analysis Molecular biology reports Low 31538301
2023 ELA (Elabela) binds APJ on brain endothelial cells and activates the YAP/TAZ signaling pathway, promoting post-ischemic cerebral angiogenesis. Silencing of APJ or pharmacological blockade of YAP abolished the pro-angiogenic effects of ELA-32 in oxygen-glucose deprivation/reoxygenation conditions. ELA-32 treatment of bEnd.3 cells under OGD/R, APJ siRNA knockdown, YAP pharmacological blockade, RNA sequencing, in vivo cerebral I/R model with CBF measurement Translational research Medium 36813109

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Pharmacological and immunohistochemical characterization of the APJ receptor and its endogenous ligand apelin. Journal of neurochemistry 377 12603839
2000 Distribution of mRNA encoding B78/apj, the rat homologue of the human APJ receptor, and its endogenous ligand apelin in brain and peripheral tissues. Biochimica et biophysica acta 287 11004481
2013 The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis. The Journal of endocrinology 269 23943882
2012 APJ acts as a dual receptor in cardiac hypertrophy. Nature 213 22810587
2008 The apelin-APJ system in heart failure: pathophysiologic relevance and therapeutic potential. Biochemical pharmacology 150 18272138
1999 Amino acid sequence and embryonic expression of msr/apj, the mouse homolog of Xenopus X-msr and human APJ. Mechanisms of development 109 10473142
2013 Apelin and its receptor APJ in cardiovascular diseases. Clinica chimica acta; international journal of clinical chemistry 105 24055369
2010 Translational promise of the apelin--APJ system. Heart (British Cardiac Society) 102 20584856
2007 Expanding role for the apelin/APJ system in physiopathology. Journal of physiology and biochemistry 93 18457011
2020 Apelin/APJ system: an emerging therapeutic target for respiratory diseases. Cellular and molecular life sciences : CMLS 91 32128601
2006 Ischemic heart failure enhances endogenous myocardial apelin and APJ receptor expression. Cellular & molecular biology letters 82 17119870
2022 The Role of Apelin-APJ System in Diabetes and Obesity. Frontiers in endocrinology 77 35355561
2017 Endothelial APLNR regulates tissue fatty acid uptake and is essential for apelin's glucose-lowering effects. Science translational medicine 76 28904225
2018 Apelin and Elabela/Toddler; double ligands for APJ/Apelin receptor in heart development, physiology, and pathology. Peptides 75 29684595
2020 Apelin/Elabela-APJ: a novel therapeutic target in the cardiovascular system. Annals of translational medicine 74 32309390
2007 Modulation of apelin and APJ receptor in normal and preeclampsia-complicated placentas. Histology and histopathology 74 17128405
2016 Apelin/APJ system and cancer. Clinica chimica acta; international journal of clinical chemistry 73 27083318
2003 APJ receptor mRNA expression in the rat hypothalamic paraventricular nucleus: regulation by stress and glucocorticoids. Journal of neuroendocrinology 71 14622440
2018 Single Cell RNA Sequencing Identifies HSPG2 and APLNR as Markers of Endothelial Cell Injury in Systemic Sclerosis Skin. Frontiers in immunology 70 30327649
2016 Apelin/APJ system: A novel therapeutic target for oxidative stress-related inflammatory diseases (Review). International journal of molecular medicine 69 27035220
2016 Apelin/APJ system: A novel promising therapy target for pathological angiogenesis. Clinica chimica acta; international journal of clinical chemistry 69 28025030
2007 Functional SNP in an Sp1-binding site of AGTRL1 gene is associated with susceptibility to brain infarction. Human molecular genetics 69 17309882
2016 Apelin/APJ system as a therapeutic target in diabetes and its complications. Molecular genetics and metabolism 68 27650065
2016 Apelin (APLN) and Apelin Receptor (APLNR) in Human Ovary: Expression, Signaling, and Regulation of Steroidogenesis in Primary Human Luteinized Granulosa Cells. Biology of reproduction 67 27683264
2003 Regulation of rat APJ receptor messenger ribonucleic acid expression in magnocellular neurones of the paraventricular and supraopric nuclei by osmotic stimuli. Journal of neuroendocrinology 66 12787050
2022 Apelin/APJ system in inflammation. International immunopharmacology 62 35605524
2019 Targeting APLN/APLNR Improves Antiangiogenic Efficiency and Blunts Proinvasive Side Effects of VEGFA/VEGFR2 Blockade in Glioblastoma. Cancer research 62 30718358
2014 Apelin-APJ signaling: a potential therapeutic target for pulmonary arterial hypertension. Molecules and cells 61 24608803
2003 Cell-cell fusion and internalization of the CNS-based, HIV-1 co-receptor, APJ. Virology 60 12667811
2020 Role of Apelin/APJ axis in cancer development and progression. Advances in medical sciences 59 32087570
2022 Targeting APLN/APJ restores blood-testis barrier and improves spermatogenesis in murine and human diabetic models. Nature communications 58 36443325
2014 The apelin-APJ system induces tumor arteriogenesis in hepatocellular carcinoma. Anticancer research 57 25275024
2013 Apelin and APJ, a novel critical factor and therapeutic target for atherosclerosis. Acta biochimica et biophysica Sinica 55 23588025
2017 Apelin/APJ system: A novel potential therapy target for kidney disease. Journal of cellular physiology 50 28796300
2021 The Elabela-APJ axis: a promising therapeutic target for heart failure. Heart failure reviews 49 32314083
2012 Apelin enhances cardiac neovascularization after myocardial infarction by recruiting aplnr+ circulating cells. Circulation research 49 22753078
2016 The apelin-APJ axis: A novel potential therapeutic target for organ fibrosis. Clinica chimica acta; international journal of clinical chemistry 48 26944568
2014 Apelin/APJ system: a promising therapy target for hypertension. Molecular biology reports 48 24990699
2009 The expression of apelin and its receptor APJ during different physiological stages in the bovine ovary. International journal of biological sciences 48 19461937
2019 Apelin/APJ system: A novel promising target for neurodegenerative diseases. Journal of cellular physiology 47 31254280
2018 Apelin/APJ system: A potential therapeutic target for endothelial dysfunction-related diseases. Journal of cellular physiology 46 30585633
2015 Apelin/APJ signaling in hypoxia-related diseases. Clinica chimica acta; international journal of clinical chemistry 46 26436483
2014 ERG-APLNR axis controls pulmonary venule endothelial proliferation in pulmonary veno-occlusive disease. Circulation 46 25062690
2015 The Emerging Potential of the Apelin-APJ System in Heart Failure. Journal of cardiac failure 45 25795508
2009 Family-based analysis of apelin and AGTRL1 gene polymorphisms with hypertension in Han Chinese. Journal of hypertension 45 19307984
2021 Adipokine Apelin/APJ Pathway Promotes Peritoneal Dissemination of Ovarian Cancer Cells by Regulating Lipid Metabolism. Molecular cancer research : MCR 44 34172534
2020 The Apelin/APJ System in Psychosis and Neuropathy. Frontiers in pharmacology 44 32231577
2016 MicroRNA 139-5p coordinates APLNR-CXCR4 crosstalk during vascular maturation. Nature communications 43 27068353
2016 Apelin/APJ System: A Novel Therapeutic Target for Myocardial Ischemia/Reperfusion Injury. DNA and cell biology 43 27854125
2016 Apelin/APJ system: A bifunctional target for cardiac hypertrophy. International journal of cardiology 43 27979574
2015 Regulation of the endothelial apelin/APJ system by hemodynamic fluid flow. Cellular signalling 43 25817266
2018 Apelin/APJ system: A novel promising target for anti-aging intervention. Clinica chimica acta; international journal of clinical chemistry 42 30296443
2010 Validation of genetic association in apelin-AGTRL1 system with hypertension in a larger Han Chinese population. Journal of hypertension 42 20485192
2023 Elabela-APJ axis attenuates cerebral ischemia/reperfusion injury by inhibiting neuronal ferroptosis. Free radical biology & medicine 41 36681202
2015 Targeting drugs to APJ receptor: the prospect of treatment of hypertension and other cardiovascular diseases. Current drug targets 41 25438973
2015 Hypoxia promotes bone marrow-derived mesenchymal stem cell proliferation through apelin/APJ/autophagy pathway. Acta biochimica et biophysica Sinica 41 25736405
2020 Cardiovascular response to small-molecule APJ activation. JCI insight 40 32208384
2015 Hypoxia induces the proliferation of endothelial progenitor cells via upregulation of Apelin/APLNR/MAPK signaling. Molecular medicine reports 39 26676468
2000 Expression and coreceptor function of APJ for primate immunodeficiency viruses. Virology 39 11040134
2019 The apelin/APJ system as a therapeutic target in metabolic diseases. Expert opinion on therapeutic targets 37 30570369
2017 Apelin/APJ axis improves angiotensin II-induced endothelial cell senescence through AMPK/SIRT1 signaling pathway. Archives of medical science : AMS 36 30002688
2018 Apelin/APJ system: A critical regulator of vascular smooth muscle cell. Journal of cellular physiology 35 29215755
2018 Function and regulation of apelin/APJ system in digestive physiology and pathology. Journal of cellular physiology 35 30390294
2017 Novel pathogenesis: regulation of apoptosis by Apelin/APJ system. Acta biochimica et biophysica Sinica 35 28407045
2015 The Apelin-APJ System in the Evolution of Heart Failure. Clujul medical (1957) 35 26528040
2017 The Role of the Apelin/APJ System in the Regulation of Liver Disease. Frontiers in pharmacology 34 28484393
2009 Maturation of blood vessels by haematopoietic stem cells and progenitor cells: involvement of apelin/APJ and angiopoietin/Tie2 interactions in vessel caliber size regulation. Thrombosis and haemostasis 34 19492139
2017 Apelin/APJ system: A key therapeutic target for liver disease. Oncotarget 33 29340118
2021 Apelin, APJ, and ELABELA: Role in Placental Function, Pregnancy, and Foetal Development-An Overview. Cells 32 35011661
2018 Apj+ Vessels Drive Tumor Growth and Represent a Tractable Therapeutic Target. Cell reports 32 30380415
2011 Non-activated APJ suppresses the angiotensin II type 1 receptor, whereas apelin-activated APJ acts conversely. Hypertension research : official journal of the Japanese Society of Hypertension 32 21412239
2005 G protein-coupled APJ receptor signaling induces focal adhesion formation and cell motility. International journal of molecular medicine 32 16211245
2023 Tubular Elabela-APJ axis attenuates ischemia-reperfusion induced acute kidney injury and the following AKI-CKD transition by protecting renal microcirculation. Theranostics 31 37351176
2019 Multifunctional APJ Pathway Promotes Ovarian Cancer Progression and Metastasis. Molecular cancer research : MCR 31 30858172
2010 Overexpression of apelin receptor (APJ/AGTRL1) on hepatic stellate cells and sinusoidal angiogenesis in human cirrhotic liver. Journal of gastroenterology 30 20725750
2021 Neuroprotective gain of Apelin/APJ system. Neuropeptides 29 33640616
2018 Targeting drugs to APJ receptor: From signaling to pathophysiological effects. Journal of cellular physiology 29 30070701
2021 Hsa_circ_0123190 acts as a competitive endogenous RNA to regulate APLNR expression by sponging hsa-miR-483-3p in lupus nephritis. Arthritis research & therapy 28 33436040
2021 Apelin/APJ relieve diabetic cardiomyopathy by reducing microvascular dysfunction. The Journal of endocrinology 28 33504680
2014 A static pressure sensitive receptor APJ promote H9c2 cardiomyocyte hypertrophy via PI3K-autophagy pathway. Acta biochimica et biophysica Sinica 28 24966188
2022 Apelin/APJ system: an emerging therapeutic target for neurological diseases. Molecular biology reports 26 36378421
2019 APLNR is involved in ATRA-induced growth inhibition of nasopharyngeal carcinoma and may suppress EMT through PI3K-Akt-mTOR signaling. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 26 31408612
2009 Apelin and its receptor APJ in human aortic valve stenosis. The Journal of heart valve disease 26 20099713
2023 ELABELA/APJ Axis Prevents Diabetic Glomerular Endothelial Injury by Regulating AMPK/NLRP3 Pathway. Inflammation 24 37540330
2020 The Protective Effects and Mechanisms of Apelin/APJ System on Ischemic Stroke: A Promising Therapeutic Target. Frontiers in neurology 24 32194492
2021 Study Progression of Apelin/APJ Signaling and Apela in Different Types of Cancer. Frontiers in oncology 23 33912466
2021 Apelin/APJ system: A novel therapeutic target for locomotor system diseases. European journal of pharmacology 23 34174264
2020 A patent review of apelin receptor (APJR) modulators (2014-2019). Expert opinion on therapeutic patents 23 32066307
2022 The Apelin/APLNR system modulates tumor immune response by reshaping the tumor microenvironment. Gene 22 35598689
2021 Impact of the apelin/APJ axis in the pathogenesis of Parkinson's disease with therapeutic potential. Journal of neuroscience research 20 34115895
2019 The biological function of ELABELA and APJ signaling in the cardiovascular system and pre-eclampsia. Hypertension research : official journal of the Japanese Society of Hypertension 20 30626933
2018 Characterization of the Apelin/Elabela Receptors (APLNR) in Chickens, Turtles, and Zebrafish: Identification of a Novel Apelin-Specific Receptor in Teleosts. Frontiers in endocrinology 19 30631305
2023 APJ as Promising Therapeutic Target of Peptide Analogues in Myocardial Infarction- and Hypertension-Induced Heart Failure. Pharmaceutics 17 37242650
2023 Elabela-APJ axis mediates angiogenesis via YAP/TAZ pathway in cerebral ischemia/reperfusion injury. Translational research : the journal of laboratory and clinical medicine 16 36813109
2020 Roles for heterodimerization of APJ and B2R in promoting cell proliferation via ERK1/2-eNOS signaling pathway. Cellular signalling 15 32407761
2019 Role of apelin/APJ system in hypothalamic-pituitary axis. Clinica chimica acta; international journal of clinical chemistry 15 31525345
2019 Apelin abrogates the stimulatory effects of 17β-estradiol and insulin-like growth factor-1 on proliferation of epithelial and granulosa ovarian cancer cell lines via crosstalk between APLNR and ERα/IGF1R. Molecular biology reports 15 31538301
2019 The influence of post-infarct heart failure and high fat diet on the expression of apelin APJ and vasopressin V1a and V1b receptors. Neuropeptides 15 31645268
2018 Apelin/APJ expression in the heart and kidneys of hypertensive rats. Acta histochemica 15 29395316
2014 The effects of water immersion and restraint stress on the expressions of apelin, apelin receptor (APJR) and apoptosis rate in the rat heart. Acta histochemica 15 24411164

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