title: Apela Regulates Fluid Homeostasis by Binding to the APJ Receptor to Activate Gi Signaling.
abstract: Apela (APJ early endogenous ligand, also known as elabela or toddler) is a recently discovered peptide hormone. Based on genetic studies in zebrafish, apela was found to be important for endoderm differentiation and heart development during embryogenesis. Although common phenotypes of apela and APJ-null zebrafish during embryonic development suggested that apela interacts with the APJ receptor, kinetics of apela binding to APJ and intracellular signaling pathways for apela remain unknown. The role of apela in adults is also uncertain. Using a chimeric apela ligand, we showed direct binding of apela to APJ with high affinity (Kd = 0.51 nm) and the ability of apelin, the known peptide ligand for APJ, to compete for apela binding. Apela, similar to apelin, acts through the inhibitory G protein pathway by inhibiting forskolin-stimulated cAMP production and by inducing ERK1/2 phosphorylation. In adult rats, apela is expressed exclusively in the kidney, unlike the wide tissue distribution of apelin. In vivo studies demonstrated the ability of apela to regulate fluid homeostasis by increasing diuresis and water intake. Dose-response studies further indicated that apela induces 2- and 5-fold higher maximal responses than apelin in ERK1/2 phosphorylation and diuresis/water intake, respectively. After designing an apela antagonist, we further demonstrated the role of endogenous ligand(s) in regulating APJ-mediated fluid homeostasis. Our results identified apela as a potent peptide hormone capable of regulating fluid homeostasis in adult kidney through coupling to the APJ-mediated Gi signaling pathway.
authors.affiliation: From the Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China and Program of Reproductive and Stem Cell Biology, Department of Ob/Gyn, Stanford University School of Medicine, Stanford, California 94305-5317.
authors.forename: Cheng
authors.initials: C
authors.lastname: Deng
authors.affiliation: From the Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China and.
authors.forename: Haidi
authors.initials: H
authors.lastname: Chen
authors.affiliation: From the Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China and.
authors.forename: Na
authors.initials: N
authors.lastname: Yang
authors.affiliation: Program of Reproductive and Stem Cell Biology, Department of Ob/Gyn, Stanford University School of Medicine, Stanford, California 94305-5317.
authors.forename: Yi
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Program of Reproductive and Stem Cell Biology, Department of Ob/Gyn, Stanford University School of Medicine, Stanford, California 94305-5317 aaron.hsueh@stanford.edu.
authors.forename: Aaron J W
authors.initials: AJ
authors.lastname: Hsueh
mesh_terms: D000818:Animals; D000073861:Apelin; D016466:CHO Cells; D003412:Cricetulus; D047108:Embryonic Development / Q000235:genetics; D019204:GTP-Binding Proteins / Q000096:biosynthesis* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006706:Homeostasis / Q000235:genetics / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism* / Q000502:physiology; D008024:Ligands; D036361:Peptide Hormones / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D014867:Water / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
chemical_list: C000595490:Apela protein, zebrafish; D000073861:Apelin; C498579:Apln protein, rat; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D036361:Peptide Hormones; D043562:Receptors, G-Protein-Coupled; D029961:Zebrafish Proteins; D014867:Water; D019204:GTP-Binding Proteins
keywords: APJ receptor; G protein; G protein-coupled receptor (GPCR); Gi pathway; apela; apelin; fluid homeostasis; homeostasis; kidney; peptide hormone