Peptides of natriuretic-diuretic activity have been identified in human and rat atrial tissues and implicated in the control of extracellular fluid volume and electrolyte homeostasis. Multiple forms of atrial natriuretic polypeptides exist, ranging in molecular weight from 3,000 to 13,000, and it has been suggested that all may derive from the same precursor (Zivin et al. 1984) . Oikawa et al. (1984) elucidated the structure of the human-alpha-ANP?s precursor and gene.
Two additional peptides showing structural homology and pharmacological properties similar to those of ANP were isolated from porcine brain. Brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), and ANP constitute the NP family (Sudoh et al. 1990, and Minamino et al. 1990). Cloning of complementary DNA indicates that the three members of the NP family are derived from different genes. The physiological activities of NPs are mediated by two specific plasma membrane receptors, guanylyl cyclase-type receptors GC-A and GC-B (Chang et al, 1989). The molecular structures of GC-A and GC-B receptors are similar (Jamison et al., 1992). The natural ligand of GC-A is ANP, whereas that of GC-B is CNP. It is thought that these pairs represent two distinct natriuretic peptide regulatory systems. The third receptor, ANP-Rc, binds all three natriuretic peptides. Its messenger RNA lacks the guanylyl cyclase sequence present in the mRNA of the other natriuretic peptide receptors, suggesting that this receptor functions to remove natriuretic peptides from the circulation and regulate plasma levels of the natriuretic peptides (Jamison et al., 1992).
NCBI Summary:
The protein encoded by this gene belongs to the natriuretic peptide family. Natriuretic peptides are implicated in the control of extracellular fluid volume and electrolyte homeostasis. This protein is synthesized as a large precursor (containing a signal peptide), which is processed to release a peptide from the N-terminus with similarity to vasoactive peptide, cardiodilatin, and another peptide from the C-terminus with natriuretic-diuretic activity. Mutations in this gene have been associated with atrial fibrillation familial type 6. This gene is located adjacent to another member of the natriuretic family of peptides on chromosome 1. [provided by RefSeq, Oct 2015]
General function
Ligand, Hormone
Comment
As reviewed by Evrard et al. (1999), the atrial natriuretic hormone is a cardiac hormone which gene and receptors are widely present in the body. Its main function is to lower blood pressure and to control electrolyte homeostasis. Its main targets are the kidney and the cardiovascular system but ANP interacts with many organs to regulate hormone secretions.
Cellular localization
Secreted
Comment
ANP promotes proliferation and inhibits apoptosis of ovarian granulosa cells by NPRA/PGRMC1/EGFR complex and improves ovary functions of PCOS rats. Zheng Q et al. (2017) Polycystic ovary syndrome (PCOS) is a complicated reproductive endocrine disease characterized by polycystic ovaries, hyperandrogenism and anovulation. It is one of the main causes of infertility. RU486 is an antagonist of progesterone receptor, and most commonly used as a contraceptive. However, whether RU486 is correlated with PCOS remains unclear. Atrial natriuretic peptide (ANP) is a small peptide with natriuretic and diuretic functions, and its availability to be used in PCOS treatment is unknown. Here, we showed that the serum ANP level was lower in PCOS patients than that in healthy women, and it was also decreased in the serum and ovarian tissues of RU486-induced PCOS rats compared with the control rats. We also found that RU486 inhibited the proliferation and promoted the apoptosis of human KGN ovarian granulosa cells by downregulating progesterone receptor membrane component 1 (PGRMC1). Meantime, ANP promoted the proliferation and inhibited the apoptosis of KGN cells through upregulating ANP receptor A (NPRA). The promotive effects of ANP on ovarian functions were mediated through the formation of an NPRA/PGRMC1/EGFR complex, which further activated MAPK/ERK signaling and transcription factor AP1. Moreover, ANP treatment reversed the PCOS symptoms, and improved the fertility of RU486-induced PCOS rats. Collectively, these findings highlight that RU486 is associated with the pathogenesis of PCOS, and ANP treatment may be a promising therapeutic option for PCOS.//////////////////
Downregulation of Natriuretic Peptide System and Increased Steroidogenesis in Rat Polycystic Ovary. Pereira VM 2014 et al.
Atrial Natriuretic Peptide (ANP) is known to regulate ovarian functions, such as follicular growth and steroid hormone production. The aim of the present study was to investigate the Natriuretic Peptide System in a rat model of chronic anovulation, the rat polycystic ovary. Adult female Wistar rats received a single subcutaneous injection of 2mg estradiol valerate to induce polycystic ovaries, while the control group received vehicle injection. Two months later, their ovaries were quickly removed and analyzed. Polycystic ovaries exhibited marked elevation of testosterone and estradiol levels compared to control ovaries. The levels of ANP and the expression of ANP mRNA were highly reduced in the polycystic ovaries compared to controls. By immunohistochemistry, polycystic ovaries showed weaker ANP staining in stroma, theca cells and oocytes compared to controls. Polycystic ovaries also had increased activity of neutral endopeptidase, the main proteolytic enzyme that degrades natriuretic peptides. ANP receptor C mRNA was reduced and ANP binding to this receptor was absent in polycystic ovaries. Collectively, these results indicate a downregulation of the natriuretic peptide system in rat polycystic ovary, an established experimental model of anovulation with high ovarian testosterone and estradiol levels. Together with previous evidence demonstrating that ANP inhibits ovarian steroidogenesis, these findings suggest that low ovarian ANP levels may contribute to the abnormal steroid hormone balance in polycystic ovaries.
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Atrial natriuretic peptide is an antiapoptotic factor for human granulosa luteinized cells with impact on the results of COH/IVF in women undergoing IVF program. Dineva J et al. Aim: To investigate human granulosa luteinized cells as a local source of atrial natriuretic peptide (ANP) and its relationship to cell viability, development of preovulatory follicles and fertilization rate of oocytes. Material and Methods: Indirect immunofluorescent technique, proANP kit, 4'6-Diamidino-2-phenylindole (DAPI)-DNA staining and Caspase-3 activity assay were used to examine localization patterns, concentrations in follicular fluids (FFl) and antiapoptotic role of ANP, respectively. Results: ANP is expressed on granulosa cells with membrane, submembrane and specific granular cytoplasmic localization. Significant differences in the mean concentrations of ANP in FFl and in the mean levels of apoptotic human granulosa luteinized cells (GLC) were found between women with high and low immunoreactive ANP expression (P < 0.05). Concentrations of ANP correlated inversely and significantly with the percentage of apoptotic GLC isolated from the same women (r = -0.2645; P < 0.05). Enhanced in vitro production of ANP by granulosa cells (after sodium nitroproside and 2Bu-cGMP treatment), as well as after treatment with human recombinant ANP was associated with significant suppression of Caspase-3 activity compared to control cells (P < 0.05). Concentrations of ANP in FFl correlated positively and significantly with the number of punctured follicles and oocytes retrieved (r = 0.44716, r = 0.57854; P < 0.05) and with the fertilization rate of oocytes in vitro (r = 0.59773; P < 0.05). Conclusion: Human granulosa luteinized cells are a local source of ANP in the preovulatory human follicle, which acts as a survival factor through cGMP signaling, and its levels in follicular fluids are positively associated with the number of punctured follicles, isolated oocytes and their fertilizability in vitro.
ANF has been shown to have hypothalamic action to alter LH release (Samson et al. 1988). Pandey et al. (1987) studied of the effect of rat atrial natriuretic factor (ANFIV102-126) on the regulation of steroidogenesis in human G-L cells in vitro: treating cells with ANF caused increases in progesterone secretion from granulosa luteal cells. The presence of both local ANP synthesis and high affinity transducing receptors in the ovaries further indicate that the peptide plays a local role in ovarian growth or steroidogenesis. (Gutkowska J et al., 1993). Also, Gutkowska et al. (1999) investigated the alterations of the NP system during follicular growth and ovulation induced by gonadotropin stimulation in the rat. It was concluded that the NP system induces and maintains fluid balance in the rapidly developing ovarian follicle. Furthermore, Tornell et al. (1990) showed that ANP, via cGMP, was shown to influence oocyte meiosis, suggesting a possible involvement of ANP and cGMP in the control of the meiotic process in rat oocytes.
Zhang M, et al reported that atrial natriuretic peptide inhibits the actions of FSH and forskolin in meiotic maturation of pig oocytes via different signalling pathways.
Zhang M, et al reported that atrial natriuretic peptide negatively regulates follicle-stimulating hormone-induced porcine oocyte maturation and cumulus expansion via cGMP-dependent protein kinase pathway.
Expression of atrial natriuretic Peptide, progesterone, apoptosis-related proteins and caspase-3 in in vitro luteinized and leptin-treated porcine granulosa cells. Dineva J et al. Objective. Our aim was to examine the expression patterns of ANP, the rate of apoptosis bcl-2 and p53 expression and caspase-3 activity and progesteron (P) production in porcine granulosa cells (pGCs) stimulated in vitro for luteinization and after treatment with leptin. Methods. Freshly isolated prepubertal pGCs were cultured as monolayers for 24 h, subsequently FSH was supplemented for 24 h, and finally LH was added to a part of the cells for 24 h to induce luteinization. The effect of leptin on in vitro luteinized pGCs was tested by the addition of 10 ng/ml human recombinant leptin (hrL) 24 h after LH administration. Indirect immunofluorescence for ANP, bcl-2 and p53 expression was used, P production was assayed by direct enzyme immunoassay (EIA) and colorimetric AcDEVD-Pna assay for caspase-3 activity was applied. Results. Stimulation of prepubertal pGCs with FSH resulted in a moderate expression of ANP and elevation in P production. When FSH treatment was followed by LH, the pronounced expression of ANP was observed in all cells. Suppressive effect of FSH and LH on p53 expression and caspase-3 activity with parallel increase in bcl-2 expression and increased P production was observed. The treatment of in vitro luteinized (FSH/LH-stimulated) pGCs with leptin did not influence the expression of ANP. However, in FSH/LH plus leptin treated cells the concomitant increase in bcl-2 expression and parallel inhibitory effect on p53 expression and caspase-3 activity was noted, compared to control cells without any significant increase in P production. Conclusion. The present data demonstrated the positive relationship between ANP expression and P production in pGCs stimulated for luteinization in vitro by FSH and LH, as well as their antiapoptotic role mediated presumably by cGMP accumulation in the luteinized pGCs. A direct anti-apoptotic effect of leptin on in vitro luteinized pGCs, without any significant modulation of P production, was documented.
Expression regulated by
FSH, LH
Comment
Identification and gene expression analyses of natriuretic peptide system in the ovary of goat (Capra hircus). Peng JY et al. (2013) Natriuretic peptides (NPs) are involved in maintaining cardiovascular and fluid homeostasis, regulating reproductive processes and bone growth, and other numerous functions. To better understand the role of NPs in goat (Capra hircus), in the present study, full-length cDNAs of goat Nppa (natriuretic peptide precursor A), Nppb (natriuretic peptide precursor B) and Nppc (natriuretic peptide precursor C), respectively encoding ANP, BNP and CNP, were cloned from adult goat heart and ovary. The putative prepropeptide ANP (prepro-ANP) and prepro-CNP share a high amino acid sequence identity with other species. Real-time PCR showed that Nppa, Nppb and Nppc were widely expressed in adult goat tissues. The mRNA expression of Nppa and Nppb in the heart was extremely higher compared with other tissues. Nppc mRNA expression in the lung and uterus was also higher than in other tissues. The expression of Nppa, Nppb and Nppc genes was examined at different ovarian follicle stages using RT-PCR. The mRNAs of Nppa and Nppb were detected in secondary follicles as well as in COCs (cumulus-oocyte-complexes) and granulosa cells of antral follicles. However, the mRNA expression of Nppc was observed throughout ovarian follicle development, and it was especially higher in granulosa cells of antral follicles. In vitro, stimulating goat granulosa cells with FSH led to an increase in the expression of Nppc by dose- and time-dependent manners and a rapid decline was induced by LH stimulation, but the expression of Nppa and Nppb did not change after FSH or LH treatment. These results suggest that Nppc is a gonadotropin-induced gene in granulosa cells of goat ovary and CNP may be involved in the regulation of ovarian follicle development and oocyte maturation.//////////////////
Gutkowska et. al. (1999) studied the hormonal regulation of the NP system during follicular growth and ovulation induced by gonadotropins eCG and hCG in the rat. After treatment, the expression level of both receptors (GC-A and GC-B) increased, and ovarian ANP and C-type natriuretic peptide (CNP) gene expression was also activated.
Ovarian localization
Cumulus, Granulosa, Theca, Stromal cells
Comment
Brain natriuretic peptide and C-type natriuretic peptide maintain porcine oocyte meiotic arrest. Zhang W 2014 et al.
Recent studies have shown that C-type natriuretic peptide (CNP) serves as a key control system during mouse oocyte maturation. We used pig models (in vitro and in vivo) to explore the role played by the natriuretic peptide family in porcine oocyte maturation. We reported the expression and location of natriuretic peptide system in different stages of porcine antral follicles. Atrial natriuretic peptide (ANP) and CNP were expressed primarily in granulosa cells, whereas brain natriuretic peptide (BNP) and natriuretic peptide receptor-B (NPRB) receptor were expressed in granulosa cells (both cumulus and mural granulosa cells) and thecal internal cells, and the natriuretic peptide receptor-A (NPRA) receptor predominantly in thecal cells. Upon in vitro culture, BNP and CNP maintained meiotic arrest of oocytes associated with cumulus cells. The expression levels of BNP, CNP, and the NPRB receptor increased upon treatment of prepubertal gilts with pregnant mare's serum gonadotropin and decreased upon subsequent human chorionic gonadotropin injection. Such dynamic changes in the expression of natriuretic peptides and their receptor paralleled the proportions of oocytes exhibiting nuclear maturation in vivo. These data indicated that BNP and CNP co-contributed to maintaining porcine meiotic arrest under physiological condition and lutenizing hormone (LH) relieved this inhibitory effect by decreasing the expression levels of BNP and CNP in vivo. Our present work, combined with previous data, improved the understanding of the oocyte meiotic arrest mechanisms and further revealed that natriuretic peptides serve as oocyte maturation inhibitor (OMI) to inhibit oocyte maturation in mammals. ? 2014 Wiley Periodicals, Inc.
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Immunoreactive ANP is present in interstitial-theca cells of the rat ovary and pig ovarian granulosa cells (Kim, 1992) The presence of immunoreactive ANP was demonstrated in follicular fluid of pig ovarian follicles and rabbit ovarian homogenates and perfusates (Kim et al., 1989). Immunocytochemical studies localized ANP to interstitial cells surrounding the follicles; weaker but specific staining was also observed in the ovum. High affinity ANP receptors were identified in ovarian membranes (Gutkowska J et al., 1993).
Tornell et al. (1990) demonstrated a dose-dependent inhibition of spontaneous maturation (resumption of meiosis) in rat oocyte-cumulus complexes by atrial natriuretic peptide (ANP). In oocytes where the surrounding cumulus cells were removed, ANP inhibited the spontaneous maturation. It was concluded that cumulus cells, but not the oocyte itself, have ANP receptors.
Localization of atrial natriuretic peptide in pig granulosa cells isolated from ovarian follicles of various size.
Ivanova MD, et al .
The aim of the current study was to present the spatial distribution of atrial natriuretic peptide (ANP) in short-term cultures of pig granulosa cells obtained from small, medium, and large ovarian follicles. The specific immunoreactivity was detected by three monoclonal antibodies recognizing different epitopes of the ANP molecule (Mab 6C3, Mab 6F11, Mab5D3). The specific ANP immunoreactivity detected by Mab 6C3 and Mab 6F11 showed dense staining of cytoplasm and was similar in granulosa cells from small and medium follicles. The strongest ANP immunostaining was observed in GC obtained from large follicles. The ANP immunostaining detected by Mab 5D3 had granular appearance moderately expressed in the submembrane region of granulosa cells of all types of follicles. Since ANP and ANP receptors are present in reproductive organs, the three anti-ANP antibodies may be an useful tool in further studies concerning the role of ANP in granulosa cell differentiation and function.
Follicle stages
Comment
Since C-type natriuretic peptide (CNP) and the guanylyl cyclase receptors A and B (GC-A and GC-B) showed coordinate estrous cycle-dependent variation with maximal expression at proestrus, it was concluded that the natriuretic peptides may play an important role in either the development of ovulatory follicles or in the ovulatory process (Jankowski et al., 1997).
Phenotypes
PCO (polycystic ovarian syndrome)
Mutations
2 mutations
Species: human
Mutation name: type: naturally occurring fertility: None Comment: Low plasma atrial natriuretic peptide: a new piece in the puzzle of polycystic ovary syndrome. Lauria PB 2013 et al.
Context:It is believed that a dysfunction in adipose tissue plays an important role in the pathogenesis of polycystic ovary syndrome (PCOS). Natriuretic peptides are hormones that regulate cardiovascular and body fluid homeostasis and adipose tissue metabolism. Natriuretic peptide levels are reduced in individuals with obesity and diabetes.Objective:This study aimed to investigate whether natriuretic peptide levels are altered in women with PCOS and if they correlate with adiponectin level or insulin sensitivity markers.Design:Cross-sectional study.Setting:Referral center in a teaching hospital.Patients or Other Participants:We evaluated 40 patients diagnosed with PCOS according to the Rotterdam criteria and 36 control women matched for age and BMI.Intervention(s):none.Main Outcome Measure(s):We measured serum adiponectin, plasma atrial natriuretic peptide (ANP) and plasma brain natriuretic peptide (BNP) using enzyme immunoassays in both groups. We evaluated metabolic markers, such as fasting glucose, insulin, total cholesterol, HDL, LDL and triglycerides. In addition, we calculated the homeostasis model assessment-insulin resistance index (HOMA-IR) and the lipid accumulation product (LAP) index and tested the linear correlations between these metabolic indices and the plasma ANP and serum adiponectin concentrations.Results:ANP and adiponectin were reduced in the PCOS group compared to the control group (p=0.010 and p=0.014, respectively). The BNP concentration did not differ between the two groups (p=0.883). There was no correlation between ANP and any of the metabolic markers. In the control group, the serum adiponectin level was inversely correlated with BMI (p=0.011), waist circumference (p=0.021), insulin (p=0.013), fasting glucose (p=0.010), HOMA-IR (p=0.007) and LAP (p=0.022). Remarkably, none of these correlations were observed in the women with PCOS.Conclusion:Women with PCOS had lower ANP and adiponectin compared to controls matched for age and BMI. Thus, the mechanisms that affect ANP and adiponectin production and clearance may be altered in PCOS, regardless of adiposity. These hormones may be involved in the metabolic features of PCOS.
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Species: mouse
Mutation name: ANP gene disruption
type: null mutation fertility: fertile Comment:John et al. (1995) generated mice with a disruption of the ANP gene. Homozygous mutants had no circulating or atrial ANP, and their blood pressures were elevated when they were fed standard and intermediate salt diets. On standard salt diets, heterozygotes had normal amounts of circulating ANP and normal blood pressures. However, on high salt diets, they were hypertensive. These results demonstrate that genetically reduced production of ANP can lead to salt-sensitive hypertension. Detection of human genetic variants that affect the function of the ANP system may identify hypertensive patients likely to benefit from reduced salt intake.