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SNAT 2 Expression and Regulation in Human Growth-Restricted Placentas

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SNAT 2 Expression and Regulation in Human Growth-Restricted Placentas nature publishing group Articles Basic Science Investigation SNAT2 expression and regulation in human growth-restricted placentas Chiara Mandò1,2, Silvia Tabano2,3, Paola Pileri1,2, Patrizia Colapietro2,4, Maria Antonella Marino1,2, Laura Avagliano2,5, Patrizia Doi2,5, Gaetano Bulfamante2,5, Monica Miozzo2,3 and Irene Cetin1,2 BACKGROUND: Amino acid placental delivery is reduced in pregnancies sampled at the time of caesarean section or at cor- human intrauterine growth–restricted (IUGR) fetuses, and the docentesis (3,4). Previous in vivo studies measured by stable activity of placental amino transporters has been consistently isotope tracers found decreased essential amino acid placen- shown to be decreased in in vitro studies. We hypothesized tal transport rates (5,6), and in vitro experiments confirmed lower placental expression and localization of sodium-cou- reduced activity of placental amino acid transport systems pled neutral amino acid transporter 2 (SNAT2 (also known as (10,11) in IUGR and small-for-gestational-age pregnancies as SLC38A2)), altered levels of intron-1 methylation, and altered compared with normal pregnancies. distribution of single-nucleotide polymorphisms in human Amino acid transporters play an important part in regu- IUGR vs. normal pregnancies. lating fetal plasma amino acid composition (12). The System METHODS: We studied 88 IUGR and 84 control placentas from A family, which contains three highly homologous protein singleton pregnancies at elective caesarean section. SNAT2 subtypes (sodium-coupled neutral amino acid transporter expression was investigated by real-time PCR and immuno- 1 (SNAT1; also known as SLC38A1), SNAT2 (also known as histochemistry. Intron-1 methylation levels were analyzed by SLC38A2), and SNAT4 (also known as SLC38A4), promotes pyrosequencing, and single-nucleotide polymorphism distri- the transport of neutral amino acids from the mother to the bution was analyzed by allelic discrimination. fetus, which is vital for the development and growth of both RESULTS: mRNA levels were significantly decreased the fetus and the placenta and may function in the transport of in IUGR placentas with reduced umbilical blood flows. amino acids at the blood–brain barrier. In particular, SNAT2 Syncytiotrophoblast immunostaining was lower in IUGR pla- is expressed both in fetus and placenta and has a crucial role centas than in control placentas. Methylation levels were in the control of fetal growth (13). A number of studies report steadily low in both IUGR and control placentas. SNP genotype reduced System A membrane activity per milligram of micro- and allele frequencies did not differ between the two groups. villous membrane in human IUGR placentas (10,14,15). Of CONCLUSION: This is the first study investigating SNAT2 note, in rats, placental Snat2 downregulation has been dem- expression and regulation mechanisms in human IUGR pla- onstrated to precede the development of intrauterine growth centas. We confirm previous results obtained in rats and cell restriction (13), suggesting that its reduction is a cause, and cultures that support the fundamental role of SNAT2 in fetal not a consequence of the disease. However, SNAT2 expression growth and well-being, as well as a possible role of oxygen lev- and regulation mechanisms have never been investigated in els in regulating SNAT2 expression, indicating the relevance of the human placental tissue. hypoxia in IUGR. Snat2 regulation is mediated by several factors (13,16–19), particularly hypoxia and amino acid extracellular concentra- educed oxygen and nutrient placental delivery has been tions. SNAT2 intron-1 is a noncoding region within the SNAT2 Rclearly demonstrated in intrauterine growth–restricted gene that spans 54 nucleotides and contains sequences that are (IUGR) pregnancies (1–7). Amino acids are needed during able to respond to amino acid deficiency and activate SNAT2 fetal growth for protein synthesis and also for energy pro- gene expression (20). Moreover, intron-1 contains CpG islands duction, supplying 20–40% of the fetal–placental unit energy (CpGs), which are repeated CG sequences in which the C requirements (8). The placenta itself consumes a large amount nucleotide is the site of DNA methylation. of amino acids, accounting for its active metabolism (9). Here, we measured SNAT2 gene expression and protein We previously reported reduced amino acid concentrations localization in human IUGR placentas compared with control as well as altered fetal–maternal amino acid gradients in IUGR placentas. We then measured methylation levels of the CpG 1Department of Biomedical and Clinical Sciences, Luigi Sacco Hospital, University of Milan, Milan, Italy; 2Center for Fetal Research Giorgio Pardi, University of Milan, Milan, Italy; 3Department of Clinical/Surgical Pathophysiology and Organ Transplant, Division of Pathology, Fondazione IRCCS Ca’ Granda–Ospedale Maggiore Policlinico, Milan, Italy; 4Department of Health Sciences, Division of Pathology, Fondazione IRCCS Ca’ Granda–Ospedale Maggiore Policlinico, Milan, Italy; 5Department of Health Sciences, San Paolo Hospital, University of Milan, Milan, Italy. Correspondence: Irene Cetin ([email protected]) Received 10 August 2012; accepted 22 January 2013; advance online publication 24 July 2013. doi:10.1038/pr.2013.83 104 Pediatric REsEarcH Volume 74 | Number 2 | August 2013 Copyright © 2013 International Pediatric Research Foundation, Inc. SNAT2 in human IUGR placentas Articles islands located within the placental SNAT2 intron-1 to verify differences in the IUGR population with gestational age rang- possible differences in methylation profile between IUGR and ing between 30 and 39 wk, representing all three groups of normal pregnancies. Finally, we investigated the association severity, we reported a significant difference in gestational with intrauterine growth restriction of a single-nucleotide age between the severity groups, but no significant correla- polymorphism (SNP) located within a SNAT2 intron-1 CpG tion between SNAT2 expression and gestational age. There island, the ancestral nucleotide of which is a cytosine belong- were no significant gender-related differences in SNAT2 gene ing to the CpG island. expression. RESULTS a Cord Blood Analysis 0.4 Blood from IUGR umbilical arteries and veins had significantly * lower pO2 than that of controls (P < 0.001) (Table 1). Similarly, oxygen saturation and content were significantly lower and 0.3 els lactate was significantly higher in IUGR umbilical veins and v arteries than in controls. These differences increased progres- sively with the severity of intrauterine growth restriction. 0.2 T2 mRNA le SNAT2 Gene Expression in IUGR and Control Placentas SNA 0.1 SNAT2 mRNA levels from 49 IUGR and 41 control placentas were analyzed by real-time PCR. SNAT2 gene expression levels were significantly lower in 0.0 IUGR placentas, with a 27% reduction compared with controls Controls IUGR (P = 0.03) (Figure 1a). However, after dividing the IUGR pla- b centas into three severity groups, SNAT2 expression levels were significantly lower than controls only in the two most severe 0.13 groups (that is, IUGR2 and IUGR3) (P = 0.007) (Figure 1b). 0.10 els SNAT2 mRNA levels decreased in relation to the oxygen v ** content in the umbilical vein, and this relation was statistically significant (P = 0.03) (Figure 1c). A significant positive rela- 0.08 tionship was observed in the study population between SNAT2 T2 mRNA le 0.05 mRNA levels and maternal age, as well as with gestational SNA age and fetal and placental weights. However, after analyzing 0.03 Table 1. Cord blood analysis in IUGR and control pregnancies 0.00 Average SD P Controls IUGR 1 IUGR 2+3 UV: pO (mm/Hg) Controls 25.9 6.7 ** c 2 0.25 IUGR 17.6 4.5 UA: pO2 (mmHg) Controls 12.5 4.1 ** 0.20 IUGR 8.1 3.5 els v UV: O2 content (mmol/l) Controls 4.0 1.8 ** IUGR 2.2 1.2 0.15 T2 mRNA le UA: O2 content (mmol/l) Controls 1.2 0.9 * SNA IUGR 0.6 0.6 0.10 UV: O2 saturation (%) Controls 45.5 19.1 ** IUGR 24.9 13.6 0.05 UA: O2 saturation (%) Controls 13.2 9.8 * 0 510 15 20 IUGR 7.4 6.2 Umbilical vein oxygen content UV: lactate (mmol/l) Controls 1.5 0.4 ** Figure 1. Sodium-coupled neutral amino acid transporter 2 (SNAT2) gene IUGR 2.2 1.3 expression. (a) SNAT2 gene expression in control and intrauterine growth– restricted (IUGR) placentas. Bars represent median values. mRNA levels in UA: lactate (mmol/l) Controls 1.7 0.6 * IUGR placentas are significantly lower compared with control placentas. IUGR 2.5 1.6 (b) SNAT2 gene expression in control and IUGR placentas divided by sever- ity. Data are presented as mean ± SE. mRNA levels decrease with IUGR IUGR, intrauterine growth–restricted; UA, umbilical artery; UV, umbilical vein. severity. (c) Significant relation between SNAT2 mRNA levels and umbilical *P < 0.05; **P < 0.001. vein oxygen content in the IUGR group. *P < 0.05 and ** P < 0.01. Copyright © 2013 International Pediatric Research Foundation, Inc. Volume 74 | Number 2 | August 2013 Pediatric REsEarcH 105 Articles Mandò et al. SNAT2 Localization in IUGR and Control Placentas (2.6 ± 0.5 and 2.8 ± 0.4, respectively), whereas the IUGR2 and SNAT2 protein was expressed in placental tissues from both IUGR3 groups had significantly lower values for both distribu- IUGR patients and controls. Cytoplasmic SNAT2 immunore- tion (1.3 ± 0.6) and intensity (1.6 ± 0.6) (P < 0.05). activity was observed in the amniotic epithelium, in the wall of the chorionic and stem vessels, and in the villous and extravil- SNAT2 Intron-1 Methylation Levels in IUGR and Control Placentas lous trophoblast. Immunostaining was present in both the Methylation analyses were conducted on DNA extracted from cyto- and syncytiotrophoblast. 37 IUGR placentas and 28 control placentas, as well as from No differences in SNAT2 spatial distribution were observed 10 peripheral blood samples taken from healthy adults, which between cases and controls in all samples examined. In our were used as external controls.
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