Elabela-Apelin Receptor Signaling Pathway is Functional in Mammalian Systems

Wang, Zhi; Yu, Dihua; Wang, Mengqiao; Wang, Qilong; Kouznetsova, Jennifer; Yang, Rongze; Qian, Kun; Wu, Wenjun; Shuldiner, Alan R.; Sztalryd, Carole; Zou, Ming-Hui; Zheng, Wei; Gong, Da-Wei

doi:10.1038/srep08170

Cited by 160 publications

(203 citation statements)

References 39 publications

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“…The trophoblast is one of the first cell lineages to differentiate after blastocyst implantation, ahead of the development of cytotrophoblasts and syncytiotrophoblasts. APELA, known to have a role in endoderm differentiation, could act as a motogen by promoting endoderm and mesoderm cells' motion during gastrulation . Highly expressed in undifferentiated embryonic stem cells, APELA is shown to trigger Apelin receptor signaling during the angioblast migration and is rapidly down‐regulated during differentiation .…”

Section: Discussionmentioning

confidence: 99%

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%

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

et al. 2019

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“…showed that ELA and apelin were detectable in healthy human plasma at subnanomolar levels, and ELA is found at significantly higher levels than apelin in the circulation. We and others found that ELA transcripts, different from apelin, are expressed mainly in pluripotent stem cells, fetal and adult kidney, prostate, and vascular endothelium, and is predominantly expressed in renal tubular epithelial cells in humans and rodents [10,12,13,27]. Our previous study demonstrated that the ELA-APJ signaling pathways are functional in mammalian systems in respect of the suppression of cAMP production, promotion of ERK phosphorylation, induction of angiogenesis, and relaxation of blood vessels.…”

Section: Discussionmentioning

confidence: 99%

“…The cDNA encoding ELA is highly conserved in vertebrates, suggesting its essential physiologic functions [12,16]. ELA shares functional similarities to apelin, another ligand of the APJ.…”

Section: Discussionmentioning

confidence: 99%

“…It acts on during embryogenesis and circulating in blood in the adult as a secreted hormonal peptide [11]. Our previous study found that ELA is exclusively expressed in human pluripotent stem cells and adult kidney and can activate APJ signaling pathways, induce angiogenesis in umbilical vascular endothelial cells, and relax mouse aortic blood vessels [12]. A recent study indicated that ELA has protective effects on ischemia-reperfusion injury in kidneys and cultured renal cells through anti-inflammatory, antiapoptotic, and antifibrotic actions [13].…”

Section: Introductionmentioning

confidence: 99%

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Serum Elabela/Toddler Levels Are Associated with Albuminuria in Patients with Type 2 Diabetes

Zhang

Gong

et al. 2018

Cell Physiol Biochem

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Background/Aims: Elabela (ELA) or Toddler is a recently identified hormone that plays a crucial role in embryonic development through the activation of the apelin receptor (APJ). Our previous study indicated that ELA is highly expressed in adult kidney and the ELA receptor signaling pathway is functional in mammalian systems. Whereas nothing is yet known regarding ELA and diabetic kidney disease (DKD). Here, we evaluated the relationship between serum ELA levels and albuminuria in patients with type 2 diabetes (T2D). Methods: An observational study involving 80 patients divided into groups according to their baseline urinary albumin/creatinine ratio (ACR): Group 1 (ACR ≤ 29 mg/g), Group 2 (ACR = 30–299 mg/g), Group 3 (ACR ≥ 300 mg/g with normal serum creatinine), and Group 4 (ACR ≥ 300 mg/g with increased serum creatinine). The demographic, clinical, and biochemical variables including serum ELA were obtained or measured through disease history, physical examination, or laboratory evidence. Results: The results showed that the serum ELA levels decreased gradually with the deterioration of DKD from the stages of normal albuminuria, microalbuminuria, macroalbuminuria, to macroalbuminuria and elevated serum creatinine. In addition, ELA had a significantly negative correlation with ACR (r = -0.561, P < 0.001), retinopathy (r = -0.424, P < 0.001), serum creatinine (r = -0.269, P = 0.016), SBP (r = -0.249, P = 0.026), DBP (r = -0.261, P = 0.020) and a positive correlation with eGFR (r = 0.318, P = 0.004). Furthermore, stepwise multiple linear regression analysis showed that ACR, retinopathy, and LDL-C were considered the most relevant variables to ELA, and ELA, retinopathy, eGFR, and age were important predictors for ACR (t = -4.546, P = 0.000). Conclusions: To our knowledge, this is the first study to explore the clinical relationship between ELA levels and CKD. Decreased serum ELA levels might be a significant clinical predictor in patients with DKD or even as a promising agent for treating CKD patients.

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“…Recently, Chng et al (2013) reported that elabela, also named as apela or toddler, is another endogenous ligand of APLNR in zebrafish, which is essential for early cardiovascular development. However, the expression of elabela is restricted to pluripotent cells and kidney in human (Wang et al, 2015). …”

Section: The Apelinergic System—apelin and Aplnrmentioning

confidence: 99%

Temporal Expression of Apelin/Apelin Receptor in Ischemic Stroke and its Therapeutic Potential

Wang

Zhou

et al. 2017

Front. Mol. Neurosci.

110

149

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Stroke is one of the leading causes of death and disability worldwide, and ischemic stroke accounts for approximately 87% of cases. Improving post-stroke recovery is a major challenge in stroke treatment. Accumulated evidence indicates that the apelinergic system, consisting of apelin and apelin receptor (APLNR), is temporally dysregulated in ischemic stroke. Moreover, the apelinergic system plays a pivotal role in post-stroke recovery by inhibiting neuronal apoptosis and facilitating angiogenesis through various molecular pathways. In this review article, we summarize the temporal expression of apelin and APLNR in ischemic stroke and the mechanisms of their dysregulation. In addition, the protective role of the apelinergic system in ischemic stroke and the underlying mechanisms of its protective effects are discussed. Furthermore, critical issues in activating the apelinergic system as a potential therapy will also be discussed. The aim of this review article is to shed light on exploiting the activation of the apelinergic system to treat ischemic stroke.

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Elabela-Apelin Receptor Signaling Pathway is Functional in Mammalian Systems

Cited by 160 publications

References 39 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

Serum Elabela/Toddler Levels Are Associated with Albuminuria in Patients with Type 2 Diabetes

Temporal Expression of Apelin/Apelin Receptor in Ischemic Stroke and its Therapeutic Potential

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