Based on peptide sequences, they cloned the corresponding human cDNA. The gene encodes a 77-amino acid polypeptide that includes a secretory signal sequence. Synthetic 36-amino acid apelin (apelin-36), corresponding to the most C-terminal 36 residues of preproapelin, caused the acidification of cells expressing transfected APJ, but not other receptors. The authors stated that apelin is an endogenous ligand for the APJ receptor. Tatemoto K, et al. 1998. Apelin has been found involved in regulating blood pressure, astrocyte-neuron interaction, inhibition of proinflammatory cytokine production, promotion of extracellular acidification, as well as GI function.
NCBI Summary:
This gene encodes a peptide that functions as an endogenous ligand for the G-protein coupled apelin receptor. The encoded preproprotein is proteolytically processed into biologically active C-terminal peptide fragments. These peptide fragments activate different tissue specific signaling pathways that regulate diverse biological functions including fluid homeostasis, cardiovascular function and insulin secretion. This protein also functions as a coreceptor for the human immunodeficiency virus 1. [provided by RefSeq, Feb 2016]
Apelin/Apelin receptor: A new therapeutic target in Polycystic Ovary Syndrome. Liu Q et al. (2020) Polycystic ovary syndrome (PCOS) is an endocrinopathy, and it accounts for 75% of non-ovulatory infertile in women of childbearing age. It is clear that obesity, insulin resistance, dyslipidaemia coexist in PCOS. Apelin, as an endogenous ligand of the previously orphan receptor, is an adipokine that secreted by adipose tissue. Apelin and apelin receptors are expressed in many tissues and organ to regulate their physiological functions. Studies have shown that Apelin/apelin-receptor also expressed in ovary such as follicles, granulosa cells. Furthermore, Apelin/apelin-receptor play roles in vascular establishment and hormone metabolism in ovary. These indicate that the Apelin/apelin-receptor play an important role in the development of follicle. Apelin/apelin-receptor are increased in ovary of PCOS, which are associated with abnormal ovarian hormones and function. These are important causes of menstrual cycle disorders and anovulation. Moreover, apelin now appears clearly as a new player in energy metabolism. Apelin can regulate glucose and lipid metabolism but also modulate insulin secretion. And plasma apelin concentrations are elevated in obesity and type 2 diabetes patients. Interestedly, obesity and type 2 diabetes are also companied with polycystic ovary syndrome patients. We speculate apelin/apelin-receptor may play a vital role in pathogenesis of polycystic ovary syndrome, but the underlying mechanisms remain under exploration. Here, we review apelin/apelin-receptor, as a new therapeutic target, have effects on ovarian function and energy metabolism in polycystic ovary syndrome.//////////////////Expression of apelin and apelin receptor (APJ) in porcine ovarian follicles and in vitro effect of apelin on steroidogenesis and proliferation through APJ activation and different signaling pathways. Rak A et al. (2017) Apelin was thought to be an adipocyte-specific hormone, but recent studies indicate a link between apelin and female reproductive function. Using real-time PCR, immunoblotting, immunohistochemistry and ELISA, we demonstrated expression of apelin and its receptor (APJ) in ovarian follicles of different sizes from mature pigs. Apelin concentration in the follicular fluid, and expression of both apelin and APJ, increased with follicular growth; greatest values were found in large follicles. Immunohistochemistry revealed the positive staining for apelin and APJ in membranes of granulosa, than theca cells. Furthermore, we observed strong expression of apelin in oocytes and APJ in the zona pellucida. The effect of apelin (0.02, 0.2, 2 and 20 ng/ml) on basal and IGF1- and FSH-induced steroid hormone (progesterone P4], and estradiol [E2]) secretion, steroidogenic enzyme (3βHSD and CYP19A1) expression and cell proliferation (Alamar blue) was determined. Apelin was found to increase basal steroid secretion, but decrease IGF1- and FSH-induced steroid secretion, and 3βHSD and CYP19 expression. Apelin also increased cell proliferation and the phosphorylation level of 5'-monophosphate-activated protein kinase (AMPK), phosphatidyl inositol 3' kinase/Akt (Akt) and extracellular signal-regulated kinases (ERK1/2). AMPKα was involved in the action of apelin in P4 production, and MAPK/ERK and Akt/PI3 mediated the proliferative effect of apelin. However, these effects on steroid secretion and cell proliferation were abolished when cultured in the presence of ML221, an APJ antagonist. In conclusion, apelin appears to regulate ovarian follicular functions such as steroidogenesis and proliferation via APJ activation and different signaling pathways.//////////////////
Apelin (APLN) regulates progesterone secretion and oocyte maturation in bovine ovarian cells. [Roche J et al. (2017) APLN and its G-protein coupled receptor APLNR are expressed in the bovine ovary. However, their role in granulosa cells and oocytes is unknown. Here, we studied their expression in bovine ovarian cells and investigated their regulation in cultured luteinizing granulosa cells in response to IGF1 and FSH. We determined the effect and the molecular mechanism of APLN (isoforms 17 and 13) on bovine granulosa cell progesterone secretion and on oocyte maturation. By RT-qPCR and immunoblot, we showed that the expression of both APLN and APLNR in granulosa and oocytes significantly increased with ovarian follicles size whereas it was similar in theca interstitial cells. In vitro, in unstimulated luteinizing bovine granulosa cells and in response to IGF1 (10-8M) but not to FSH (10-8M), we observed that APLN (-17 and -13) (10-9M) increased progesterone production; this was abolished in response to the APLNR antagonist ML221. These latter effects were dependent on the MAPK ERK1/2 kinase. Furthermore, we showed that APLN (-17 and -13) (10-9M) increased cell proliferation through AKT signaling. Conversely, the addition of APLN-13 and APLN-17 to in vitro maturation medium containing IGF1 (10-8M) but not FSH (10-8M) arrested most oocytes at the germinal vesicle stage, which was associated with a decrease in progesterone secretion, an inhibition in MAPK ERK1/2 phosphorylation and an increase in PRKA phosphorylation in oocytes. Thus, APLN can increase progesterone secretion and cell proliferation in bovine luteinizing granulosa cells in vitro, while it blocks meiotic progression at the germinal vesicle stage during bovine oocyte in vitro maturation.//////////////////
Apelin (APLN) and Apelin Receptor (APLNR) in Human Ovary: Expression, Signaling, and Regulation of Steroidogenesis in Primary Human Luteinized Granulosa Cells. Roche J et al. (2016) Apelin (APLN) is a recently discovered adipokine involved in the regulation of various metabolic functions. Its receptor, APLNR, is expressed in reproductive tissues, however, its role in human ovarian cells is unknown. In this study we identified APLN and APLNR in human ovarian follicles and analyzed their expression in granulosa cells and follicular fluid obtained from obese and non-obese patients, with or without polycystic ovary syndrome (PCOS). We also investigated the effect of APLN on steroidogenesis in cultured human luteinized granulosa cells (hGCs) from non-obese patients without PCOS. Using RT-PCR and immunoblotting we found that APLN and APLNR were expressed in hGCs and cumulus and theca cells. We confirmed these data immunohistochemically, and observed that APLNR and APLN are present in human oocytes at different stages of follicular development. In patients with PCOS, we observed that follicular fluid APLN concentration and granulosa cell APLN and APLNR mRNA expression was higher than that observed in control patients. In cultured hGCs from non-obese patients without PCOS, insulin-like growth factor (IGF)-1 increased APLNR expression, and recombinant human (rh) APLN (APLN-13 and APLN-17) increased both basal and IGF1-induced steroid secretion. These effects on steroid production were reversed when cultured in the presence of ML221, an APLNR antagonist, which was associated with an increased 3β-hydrosteroid dehydrogenase (HSD3B) protein concentration. We showed that these effects were dependent on the activation of the AKT and MAPK3/1 pathways using pharmacological inhibitors. Our results show that APLN and APLNR are present in human ovarian cells, and APLN increases IGF1-induced steroidogenesis in granulosa cells through an increase in HSD3B protein expression and activation of the MAPK3/1 and Akt pathways. Therefore, APLN and APLNR may play a role in human follicular development and the pathogenesis of PCOS.//////////////////
Effects of apelin on proliferation and apoptosis in rat ovarian granulosa cells. Shuang L et al. (2016) To investigate the influence of apelin on proliferation and apoptosis in rat ovarian granulosa cells (GCs) in vitro. Primary culture of SD rat ovarian GCs was cultured with different concentrations of apelin 10(-8) mol/L, and APJ expression in GCs was inhibited by small RNA interfering (siRNA). Signaling inhibitor LY294002 of PI3K/Akt, HIMO intervention, MTT assay and flow cytometry were combined to observe the cell proliferation and apoptosis; Western blot was used to detect signaling protein expression related with cell apoptosis. Compared with the control group, the differences on cell proliferation rate detected by MTT assay in APJ-siRNA group, LY294002 group, and HIMO group had statistical significance (p < 0.05). Protein expressions of Bad, Bax, and Foxo3a in GCs in APJ-siRNA group, LY294002 group, and HIMO group were apparently upregulated (p < 0.05), and the protein expression of Bcl-2 in APJ-siRNA group, LY294002 group, and HIMO group was obviously downregulated (p < 0.05). Apelin can promote proliferation of GCs and inhibit apoptosis via PI3/Akt signaling pathway.//////////////////
Expression regulated by
LH, Steroids
Comment
Apelin (APLN) and Apelin Receptor (APLNR) in Human Ovary: Expression, Signaling, and Regulation of Steroidogenesis in Primary Human Luteinized Granulosa Cells. Roche J et al. (2016) Apelin (APLN) is a recently discovered adipokine involved in the regulation of various metabolic functions. Its receptor, APLNR, is expressed in reproductive tissues, however, its role in human ovarian cells is unknown. In this study we identified APLN and APLNR in human ovarian follicles and analyzed their expression in granulosa cells and follicular fluid obtained from obese and non-obese patients, with or without polycystic ovary syndrome (PCOS). We also investigated the effect of APLN on steroidogenesis in cultured human luteinized granulosa cells (hGCs) from non-obese patients without PCOS. Using RT-PCR and immunoblotting we found that APLN and APLNR were expressed in hGCs and cumulus and theca cells. We confirmed these data immunohistochemically, and observed that APLNR and APLN are present in human oocytes at different stages of follicular development. In patients with PCOS, we observed that follicular fluid APLN concentration and granulosa cell APLN and APLNR mRNA expression was higher than that observed in control patients. In cultured hGCs from non-obese patients without PCOS, insulin-like growth factor (IGF)-1 increased APLNR expression, and recombinant human (rh) APLN (APLN-13 and APLN-17) increased both basal and IGF1-induced steroid secretion. These effects on steroid production were reversed when cultured in the presence of ML221, an APLNR antagonist, which was associated with an increased 3β-hydrosteroid dehydrogenase (HSD3B) protein concentration. We showed that these effects were dependent on the activation of the AKT and MAPK3/1 pathways using pharmacological inhibitors. Our results show that APLN and APLNR are present in human ovarian cells, and APLN increases IGF1-induced steroidogenesis in granulosa cells through an increase in HSD3B protein expression and activation of the MAPK3/1 and Akt pathways. Therefore, APLN and APLNR may play a role in human follicular development and the pathogenesis of PCOS.//////////////////
The expression of apelin and its receptor APJ during different physiological stages in the bovine ovary. Schilffarth S et al. Recent studies implicate that apelin and its receptor APJ may have important role for the modulation of angiogenesis. The aim of this study was to further characterise the regulation of apelin/APJ system in bovine ovary. Experiment 1: corpora lutea (CL) were assigned to the following stages: days 1-2, 3-4, 5-7, 8-12, 13-16, >18 (after regression) of oestrous cycle and of gravidity (month <3, 3-5, 6-7 and >8). Experiment 2: Follicles during maturation were divided into granulosa cells (GC) and theca interna (TI) and were examined separately. Classification of follicles occurred by follicle size and oestradiol-17beta (E2) concentration in the follicular fluid (FF) (<0.5 ng/ml, 0.5-5 ng/ml; 5-40 ng/ml; 40-180 ng/ml; >180 ng/ml). Real-time RT-PCR (qPCR) was applied to investigate mRNA expression of examined factors. In general, the expression level of apelin during the oestrous cycle was significantly higher compared to the one during pregnancy. Apelin mRNA levels were always high during the cycle with a tendency of decrease after CL regression. The APJ mRNA in the CL was significantly up regulated on days 5-7 and 8-12 followed by a decrease on days 13-16, and further on days >18. The expression of APJ does not show any significant regulation in the CL throughout pregnancy. The expression of apelin and APJ was not statistically regulated in GC, but was significantly up regulated in follicles with an E2 concentration of more than 5 ng/ml and showed an increase according to growth and maturation of follicles. In conclusion, our data suggest that apelin/APJ system is involved in the mechanism regulating angiogenesis during follicle maturation as well as during CL formation and function in the bovine ovary.
Ovarian localization
Cumulus, Granulosa, Theca, Luteal cells
Comment
Apelin and apelin receptor at different stages of corpus luteum development and effect of apelin on progesterone secretion and 3β-hydroxysteroid dehydrogenase (3β-HSD) in pigs. Różycka M et al. (2018) Recent studies have suggested that apelin has a role in controlling female reproduction. The aims of the present study were, firstly, to investigate the gene expression (mRNA and protein) and immunolocalization of apelin and its receptor APJ in corpora lutea (CL) of pigs collected during the early (CL1), middle (CL2) and late (CL3) luteal phase. Using real time PCR and immunoblotting techniques, it was observed that apelin gene expression was similar in CL1 and CL2, and less in CL3, while relative abundance APJ mRNA and abundance of the protein were similar in CL1 and CL3 and greater in CL2. There was apelin staining in the cytoplasm of both small (SC) and large (LC) luteal cells with the greatest intensity in CL2. In the cytoplasm of CL1, only a few SC cells stained for APJ; in CL2, APJ was located in the cell membrane of LC and in the cytoplasm of SC; and in CL3 was located in the membrane with moderate cytoplasmic APJ staining. Intense APJ staining was noted in epithelium of blood vessels of CL2-3. Secondly, there was an effect of apelin on progesterone (P4) secretion in CL2 and on the molecular mechanisms of these cells. Stimulatory effects of apelin on P4 secretion, 3β-hydroxysteroid dehydrogenase (HSD) activity and protein abundance were observed and this was inhibited in response to APJ and adenosine 5'-monophosphate-activated protein kinase (AMPKα) kinase blockers. In conclusion, the presence of apelin/APJ in the CL of pigs and stimulatory effects of apelin on P4 secretion and 3β-HSD levels suggest potential auto/paracrine regulation by apelin in the luteal phase of the estrous cycle. Moreover, the involvement of APJ and AMPKα kinase in apelin activity in CL was confirmed.//////////////////
This gene is expressed in mouse provoulatory follicles based on DNA array analyses. Other investigators also discussed the apelin tissue distribution that both apelin and its receptor lightly expressed in mouse and rat ovary. See Kawamata Y, et al. (Biochim Biophys Acta. 2001) and Medhurst AD, et al. (J Neurochem. 2003).
Apelin and APJ receptor expression in granulosa and theca cells during different stages of follicular development in the bovine ovary: Involvement of apoptosis and hormonal regulation. Shimizu T et al. In the mammalian ovary, the microvasculature in the thecal layer of follicles is associated with follicular development. Apelin and its receptor, APJ, are expressed in the tissues and organs which include the vasculature. The aims of the present study were to examine the mRNA expression of apelin and the APJ receptor in granulosa cells and theca tissue of bovine follicles and the effects of steroid hormone and gonadotrophins on the expression of these genes in cultured granulosa cells and theca cells. The expression of apelin mRNA was not found in the granulosa cells of bovine follicles. The expression of the APJ gene was increased in granulosa cells of estrogen-inactive dominant follicles. The expression of apelin mRNA increased in theca tissues of estrogen-inactive dominant follicles. APJ expression in theca tissues increased with follicle growth. Progesterone stimulated the expression of APJ mRNA in the cultured granulosa cells. FSH stimulated the expression of APJ mRNA in the cultured granulosa cells. LH induced the expression of apelin and APJ receptor mRNAs in cultured theca cells. Taken together, our data indicate that the APJ receptor in granulosa cells and both apelin and the APJ receptor in theca tissues are expressed in bovine ovary, that APJ in granulosa cells may be involved in the appearance of the cell apoptosis, and that LH stimulates the expression of apelin and APJ genes in theca cells.
Follicle stages
Corpus luteum
Comment
Expression and localization of apelin and its receptor APJ in the bovine corpus luteum during the estrous cycle and prostaglandin F2alpha-induced luteolysis. Shirasuna K et al. Angiogenesis, changes in blood flow, and extracellular matrix remodeling are the processes associated with the development and demise of the bovine corpus luteum (CL) during the estrous cycle. APJ (putative receptor protein related to angiotensin type 1 receptor) is a G-protein-coupled receptor, and its ligand, apelin, has been identified as a novel regulator of blood pressure and as an angiogenic factor. We hypothesized that the apelin-APJ system is involved in luteal function. This study investigated whether apelin-APJ exists in bovine CL and determined their expression profiles and localization during luteal phase and prostaglandin F(2)(alpha) (PGF(2)(alpha))-induced luteolysis. During the luteal phase, apelin mRNA expression increased from early to late CL and decreased in regressed CL. APJ mRNA expression increased from early to mid-CL and remained elevated in late and regressed CL. Apelin and APJ proteins were immunohistochemically detected only in the smooth muscle cells of intraluteal arterioles during the luteal phase. PGF(2)(alpha) stimulated apelin and APJ mRNA expression at 0.5-2 and 2 h respectively, and then the mRNA expression of apelin-APJ was inhibited from 4 h during PGF(2)(alpha)-induced luteolysis. Additionally, apelin mRNA and protein were stimulated at 1 h after PGF(2)(alpha) injection only in the periphery of mid- but not early CL. The present study indicated that the apelin-APJ was localized in the smooth muscle cells of intraluteal arterioles, and responded to PGF(2)(alpha) at the periphery of mid-CL in the cow. Thus, the apelin-APJ system may be involved in the maturation of CL and the luteolytic cascade as a regulator of intraluteal arterioles in cow.
Phenotypes
PCO (polycystic ovarian syndrome)
Mutations
1 mutations
Species: human
Mutation name: None
type: None fertility: subfertile Comment: Lower serum apelin levels in women with polycystic ovary syndrome. Chang CY et al. We tested differences in serum apelin levels between women with polycystic ovary syndrome (PCOS) and those with a healthy regular menstrual cycle, finding that apelin levels were higher in normal women and that apelin was positively correlated with apolipoprotein A levels.