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Characterisation of the Apelin Receptor and its Endogenous Ligands, Apelin and Elabela/Toddler in the Cardio-Renal System



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The apelin system is emerging as an important therapeutic target in several diseases. It comprises a G protein-coupled receptor, the apelin receptor, which binds two peptide ligands, namely apelin and Elabela/Toddler (ELA). Although apelin has been studied in some detail, little is known about the expression and function of ELA, and the renal apelin system. The aim of this study was to characterise the expression of ELA relative to apelin and apelin receptor in mouse and human tissues; to identify specific isoforms of ELA produced in human tissues and metabolites of ELA-32 in plasma and kidney homogenate, as well as determining [Pyr1]apelin-13 metabolites generated in vivo in humans. ELA mRNA was expressed in mouse and human brain, lung, heart and kidney, but both apelin and ELA mRNA were absent in the spleen and liver where only the receptor mRNA was detected. Additionally, the expression of the apelin system at the protein level is poorly defined in the kidney. Within the human kidney, apelin, ELA and apelin receptor were expressed from glomerulus to the collecting duct of the renal nephron with robust localisation of the receptor to juxtaglomerular apparatus involved in systemic blood pressure regulation. Importantly, in models of kidney disease, the expression of both ligands were downregulated, but the receptor was not altered. In chronic kidney disease patients, plasma levels of both apelin and ELA were elevated. Using a highly sensitive LC-MS/MS approach, endogenous ELA-11 was detected in human tissues for the first time. Also, novel isoforms of mature ELA-32 generated in human plasma and kidney homogenates, including ELA-11, ELA-16 and ELA-19 but not ELA-21, were found. In humans in vivo, the ACE2 metabolite [Pyr1]apelin-13(1-12) was the most abundant metabolite of [Pyr1]apelin-13 produced. Other potentially functional metabolites including [Pyr1]apelin-13(1-10) and [Pyr1]apelin-13(1-6) were also identified. This thesis demonstrated that Elabela/Toddler was not a renal-specific peptide as initially thought and identified enzymatically generated isoforms of ELA and apelin produced in human plasma. A novel distribution of the apelin system in human kidney was found, supporting the hypothesis that the apelin system may have other yet unexplored functions in the kidney beside regulation of renal fluid homeostasis. Taken together, these data suggest that the apelin system may be a novel therapeutic target for the treatment of cardiorenal diseases.





Davenport, Anthony P
Maguire, Janet J


Apelin receptor, Elabela/Toddler, Apelin system, Cardiorenal disease, G protein coupled receptor


Doctor of Philosophy (PhD)

Awarding Institution

University of Cambridge
Wellcome Trust Cambridge Trust