BackgroundNectins are cell adhesion molecules that play a pivotal role in adherens junctions and tight junctions. Our previous study using whole-genome oligonucleotide microarrays revealed that nectin-4 was upregulated in pre-eclamptic placentas. We investigated the role of nectin-4 in the etiology of pre-eclampsia.MethodsWe investigated the expression of nectin-4 using real-time RT–PCR, western blot and immunostaining. Additionally, we performed matrigel invasion assay and cytotoxicity assay using cells overexpressing the nectin-4.ResultsNECTIN4 transcripts were elevated in pre-eclamptic placentas relative to uncomplicated pregnancies. Nectin-4 protein levels in pre-eclamptic placentas were higher on a semi-quantitative western blot. Nectin-4 was localized at the apical cell membrane in syncytiotrophoblast cells and not at the adherens junctions. Nectin-4 was also detected in cytotrophoblasts and a subset of cells in the decidua. Nectin-4 overexpressing trophoblast cells migrated normally in the matrix. However, Natural killer (NK) cells showed a strong cytotoxic effect against nectin-4 overexpressing trophoblast cells. No causative genetic variation was evident in the NECTIN4 gene from a pre-eclamptic placenta.ConclusionsThere are as yet unknown factors that induce nectin-4 overexpression in trophoblast cells that may contribute to abnormal placentation via an aberrant immune response and the onset of a pre-eclamptic pregnancy.Electronic supplementary materialThe online version of this article (10.1186/s12881-018-0681-y) contains supplementary material, which is available to authorized users.
Background: Soluble fms-like tyrosine kinase 1 (sFlt-1) is believed to be a prominent component in the pathogenesis of pre-eclampsia, although the precise etiology has remained elusive. In this study, the etiological role of FLT1 variant was further validated in pre-eclampsia by examining this association in a Japanese sample population. Methods: The genotypes of three variants (rs4769613, rs12050029 and rs149427560) were examined in the upstream region of the FLT1 gene in placentas from pre-eclamptic (n=47) or normotensive control (n=49) pregnancy samples. Additionally, FLT1 mRNA levels in placenta were determined by qRT-PCR. ELISA was further used to detect circulating sFlt-1 levels in maternal sera. The intergroup comparisons were made using the Mann-Whitney U test or one way analysis of variance and P values of less than 0.05 were considered statistically significant. Results: First, the rs4769613 (C>T) and rs12050029 (G>A) genotypes were examined in placentas but no significant differences were found in the genotype or allele-type frequencies. Next, nearby short tandem repeat, rs149427560, was examined which manifested four size variants. In the genotypewise analysis, the frequency of the 474/476 heterozygote was significantly lower in pre-eclampsia (p<0.05). As expected, the FLT1 mRNA levels were significantly elevated in the pre-eclamptic placentas and sFlt-1 was higher in pre-eclamptic maternal sera. However, the genotype of these variants did not affect the FLT1 mRNA or serum sFlt-1 levels. Conclusion: Our findings did not support the hypothesis that genetic variations around the FLT1 gene affect the subtle expression changes underlying the etiologic pathway of pre-eclampsia. The hypothesis deserves further investigation through a larger sample size.
Background: FLT1 is one of the significantly overexpressed genes found in a pre-eclamptic placenta and is involved with the etiology of this disease. Methods: We conducted genome-wide expression profiling by RNA-seq of placentas from women with pre-eclampsia and those with normotensive pregnancy. Results: We identified a lncRNA gene, MG828507, located ~80 kb upstream of the FLT1 gene in a head-to-head orientation, which was overexpressed in the pre-eclamptic placenta. MG828507 and FLT1 are located within the same topologically associated domain in the genome. The MG828507 mRNA level correlated with that of the FLT1 in placentas from pre-eclamptic women as well as in samples from uncomplicated pregnancies. However, neither the overexpression nor knockdown of MG828507 affected the expression of FLT1. Analysis of pre-eclampsia-linking genetic variants at this locus suggested that the placental genotype of one variant was associated with the expression of MG828507. The MG828507 transcript level was not found to be associated with maternal blood pressure, but showed a relationship with birth and placental weights, suggesting that this lncRNA might be one of the pivotal placental factors in pre-eclampsia. Conclusion: Further characterization of the MG828507 gene may elucidate the etiological roles of the MG828507 and FLT1 genes in pre-eclampsia in a genomic context.
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