Apela Regulates Fluid Homeostasis by Binding to the APJ Receptor to Activate Gi Signaling

Deng, Cheng; Chen, Haidi; Yang, Na; Feng, Yi; Hsueh, Aaron J. W.

doi:10.1074/jbc.m115.648238

Cited by 95 publications

(152 citation statements)

References 36 publications

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“…Being an early embryonic regulator of cellular movement with a critical role in migration and development of cardiac progenitor cells, APELA has also been shown in rodent models to delay development of systemic hypertension and preserve cellular architecture in key organs such as kidney . Human endogenous APELA was predominantly expressed in kidneys, especially in renal collecting ducts, adjusting diuresis to adapting to the pregnancy . APELA was proved to exert a direct effect on the maternal endothelium, stimulating vasodilatory mechanisms such as nitric oxide production to regulate cardio‐renal function .…”

Section: Discussionmentioning

confidence: 99%

“…29 Human endogenous APELA was predominantly expressed in kidneys, especially in renal collecting ducts, adjusting diuresis to adapting to the pregnancy. 30 APELA was proved to exert a direct effect on the maternal endothelium, stimulating vasodilatory mechanisms such as nitric oxide production to regulate cardio-renal function. 29 Previous studies have shown that embryos died of cardiovascular developmental defects in early pregnancy with APELA deficient mothers.…”

Section: Discussionmentioning

confidence: 99%

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Variants in the 5'‐UTR of APELA gene in women with preeclampsia

et al. 2019

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Objective To detect APELA gene variants in clinical cases with preeclampsia (PE) and evaluate the influence of the APELA variants in gene expression. Method A total of 288 individuals suffering from PE and 384 unaffected individuals were chosen for case‐control studies. Genomic DNA was extracted from peripheral blood. Variants screening of APELA gene was conducted, and potential influence of variants in APELA expression was evaluated with a luciferase assay. Results Two rare variants (c.‐306A > G and c.‐145A > G) in the 5'‐UTR of APELA gene were identified exclusively in PE affected individuals. Luciferase assays in HEK293 cells and HTR‐8/SVneo cells revealed that both variants impaired transcriptional activity of APELA by altering the function of promoter region. Also, a single‐nucleotide polymorphism (SNP) (c.159 T > C) in exon 2 of APELA was found in both cases and controls, and there was no statistically significant difference in genotype and allele frequency between cases and controls. Conclusion Variants in the 5'‐UTR of APELA gene may account for variability of APELA expression among individuals with PE and may play a negative regulatory role in the pathogenesis of PE.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Variants in the 5'‐UTR of APELA gene in women with preeclampsia

et al. 2019

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“…Indeed, the six N ‐terminal amino acids appear less crucial for receptor interaction, suggesting that apelin‐13 and ELA(19–32) interact differently in the orthosteric binding pocket of the apelin receptor. By analogy to previous works conducted on apelin‐13, Deng et al synthesized and characterized several C ‐terminally modified analogues of ELA(12–32), an N ‐terminally truncated derivative of ELA, where Phe31 and Pro32 residues were replaced by Ala . The Pro32Ala analogue dose‐dependently reduced the effects of ELA on cAMP inhibition as well as phosphorylation by ERKs.…”

Section: Structure–activity Relationship Of Elabelamentioning

confidence: 99%

Apelins, ELABELA, and their derivatives: Peptidic regulators of the cardiovascular system and beyond

et al. 2018

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The apelinergic system emerges as an important regulator of cardiovascular functions via its actions on the heart, vasculature, and kidney. It also possesses additional beneficial properties, via its actions on the pancreas and skeletal muscle, on type 2 diabetes. The apelinergic system distinguishes itself by the presence of two structurally distinct sets of endogenous ligands, the Apelins (–13, −17, and −36) and Elabela, which both activate the apelin (APJ) receptor. In the past decade, numerous peptidic ligands have been used to better understand the structure–activity relationship of apelin (and more recently Elabela), providing important tools to rationalize how ligand modifications impact receptor structure and dynamics as well as its downstream signaling. The recently disclosed structure of the apelin receptor in complex with an analogue of apelin‐17 provides an important tool in this quest. In this review, we first summarize the physiopharmacology of the apelinergic system, then, review existing knowledge on the various ligands of the apelin receptor with an emphasis on peptidic ligands, although small molecules are covered as well. Throughout this work, we tried to integrate existing knowledge of ligands’ pharmacological profiles with structure and signaling profile.

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“…Fluid overload plays a key role in the development of HF and the participation of apelin in the regulation of fluid homeostasis has been well established [17,20,21]. ELA expression is detected in renal collecting tubules, suggesting that it has potential biological effects on fluid homeostasis [22]. It has been reported that both ELA and apelin increased urine flow rates in rats, and ELA injection induced approximately 5-fold higher maximal increases in the plateau responses of urine flow rates than apelin.…”

Section: The Ela-apj Axis and Humoral Regulationmentioning

confidence: 99%

“…Notably, ELA and apelin share the same receptor and exert similar biological effects. Therefore, a family consisting of ELA, apelin, and APJ named the apelinergic system plays cardiotonic, diuretic, depressor, and cardiorenal protective roles (Table 1) [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28]. The underlying mechanisms of the ELA-APJ axis remain largely unclear despite their clinical importance.…”

Section: Introductionmentioning

confidence: 99%

The Elabela-APJ axis: a promising therapeutic target for heart failure

Song

Martin

et al. 2020

Heart Fail Rev

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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.

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Apela Regulates Fluid Homeostasis by Binding to the APJ Receptor to Activate Gi Signaling

Cited by 95 publications

References 36 publications

Variants in the 5'‐UTR of APELA gene in women with preeclampsia

Variants in the 5'‐UTR of APELA gene in women with preeclampsia

Apelins, ELABELA, and their derivatives: Peptidic regulators of the cardiovascular system and beyond

The Elabela-APJ axis: a promising therapeutic target for heart failure

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