Cargando…
Identification of placental nutrient transporters associated with intrauterine growth restriction and pre-eclampsia
BACKGROUND: Gestational disorders such as intrauterine growth restriction (IUGR) and pre-eclampsia (PE) are main causes of poor perinatal outcomes worldwide. Both diseases are related with impaired materno-fetal nutrient transfer, but the crucial transport mechanisms underlying IUGR and PE are not f...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833046/ https://www.ncbi.nlm.nih.gov/pubmed/29499643 http://dx.doi.org/10.1186/s12864-018-4518-z |
_version_ | 1783303413024423936 |
---|---|
author | Huang, Xiao Anderle, Pascale Hostettler, Lu Baumann, Marc U. Surbek, Daniel V. Ontsouka, Edgar C. Albrecht, Christiane |
author_facet | Huang, Xiao Anderle, Pascale Hostettler, Lu Baumann, Marc U. Surbek, Daniel V. Ontsouka, Edgar C. Albrecht, Christiane |
author_sort | Huang, Xiao |
collection | PubMed |
description | BACKGROUND: Gestational disorders such as intrauterine growth restriction (IUGR) and pre-eclampsia (PE) are main causes of poor perinatal outcomes worldwide. Both diseases are related with impaired materno-fetal nutrient transfer, but the crucial transport mechanisms underlying IUGR and PE are not fully elucidated. In this study, we aimed to identify membrane transporters highly associated with transplacental nutrient deficiencies in IUGR/PE. RESULTS: In silico analyses on the identification of differentially expressed nutrient transporters were conducted using seven eligible microarray datasets (from Gene Expression Omnibus), encompassing control and IUGR/PE placental samples. Thereby 46 out of 434 genes were identified as potentially interesting targets. They are involved in the fetal provision with amino acids, carbohydrates, lipids, vitamins and microelements. Targets of interest were clustered into a substrate-specific interaction network by using Search Tool for the Retrieval of Interacting Genes. The subsequent wet-lab validation was performed using quantitative RT-PCR on placentas from clinically well-characterized IUGR/PE patients (IUGR, n = 8; PE, n = 5; PE+IUGR, n = 10) and controls (term, n = 13; preterm, n = 7), followed by 2D-hierarchical heatmap generation. Statistical evaluation using Kruskal-Wallis tests was then applied to detect significantly different expression patterns, while scatter plot analysis indicated which transporters were predominantly influenced by IUGR or PE, or equally affected by both diseases. Identified by both methods, three overlapping targets, SLC7A7, SLC38A5 (amino acid transporters), and ABCA1 (cholesterol transporter), were further investigated at the protein level by western blotting. Protein analyses in total placental tissue lysates and membrane fractions isolated from disease and control placentas indicated an altered functional activity of those three nutrient transporters in IUGR/PE. CONCLUSIONS: Combining bioinformatic analysis, molecular biological experiments and mathematical diagramming, this study has demonstrated systematic alterations of nutrient transporter expressions in IUGR/PE. Among 46 initially targeted transporters, three significantly regulated genes were further investigated based on the severity and the disease specificity for IUGR and PE. Confirmed by mRNA and protein expression, the amino acid transporters SLC7A7 and SLC38A5 showed marked differences between controls and IUGR/PE and were regulated by both diseases. In contrast, ABCA1 may play an exclusive role in the development of PE. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12864-018-4518-z) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5833046 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-58330462018-03-05 Identification of placental nutrient transporters associated with intrauterine growth restriction and pre-eclampsia Huang, Xiao Anderle, Pascale Hostettler, Lu Baumann, Marc U. Surbek, Daniel V. Ontsouka, Edgar C. Albrecht, Christiane BMC Genomics Research Article BACKGROUND: Gestational disorders such as intrauterine growth restriction (IUGR) and pre-eclampsia (PE) are main causes of poor perinatal outcomes worldwide. Both diseases are related with impaired materno-fetal nutrient transfer, but the crucial transport mechanisms underlying IUGR and PE are not fully elucidated. In this study, we aimed to identify membrane transporters highly associated with transplacental nutrient deficiencies in IUGR/PE. RESULTS: In silico analyses on the identification of differentially expressed nutrient transporters were conducted using seven eligible microarray datasets (from Gene Expression Omnibus), encompassing control and IUGR/PE placental samples. Thereby 46 out of 434 genes were identified as potentially interesting targets. They are involved in the fetal provision with amino acids, carbohydrates, lipids, vitamins and microelements. Targets of interest were clustered into a substrate-specific interaction network by using Search Tool for the Retrieval of Interacting Genes. The subsequent wet-lab validation was performed using quantitative RT-PCR on placentas from clinically well-characterized IUGR/PE patients (IUGR, n = 8; PE, n = 5; PE+IUGR, n = 10) and controls (term, n = 13; preterm, n = 7), followed by 2D-hierarchical heatmap generation. Statistical evaluation using Kruskal-Wallis tests was then applied to detect significantly different expression patterns, while scatter plot analysis indicated which transporters were predominantly influenced by IUGR or PE, or equally affected by both diseases. Identified by both methods, three overlapping targets, SLC7A7, SLC38A5 (amino acid transporters), and ABCA1 (cholesterol transporter), were further investigated at the protein level by western blotting. Protein analyses in total placental tissue lysates and membrane fractions isolated from disease and control placentas indicated an altered functional activity of those three nutrient transporters in IUGR/PE. CONCLUSIONS: Combining bioinformatic analysis, molecular biological experiments and mathematical diagramming, this study has demonstrated systematic alterations of nutrient transporter expressions in IUGR/PE. Among 46 initially targeted transporters, three significantly regulated genes were further investigated based on the severity and the disease specificity for IUGR and PE. Confirmed by mRNA and protein expression, the amino acid transporters SLC7A7 and SLC38A5 showed marked differences between controls and IUGR/PE and were regulated by both diseases. In contrast, ABCA1 may play an exclusive role in the development of PE. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12864-018-4518-z) contains supplementary material, which is available to authorized users. BioMed Central 2018-03-02 /pmc/articles/PMC5833046/ /pubmed/29499643 http://dx.doi.org/10.1186/s12864-018-4518-z Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Huang, Xiao Anderle, Pascale Hostettler, Lu Baumann, Marc U. Surbek, Daniel V. Ontsouka, Edgar C. Albrecht, Christiane Identification of placental nutrient transporters associated with intrauterine growth restriction and pre-eclampsia |
title | Identification of placental nutrient transporters associated with intrauterine growth restriction and pre-eclampsia |
title_full | Identification of placental nutrient transporters associated with intrauterine growth restriction and pre-eclampsia |
title_fullStr | Identification of placental nutrient transporters associated with intrauterine growth restriction and pre-eclampsia |
title_full_unstemmed | Identification of placental nutrient transporters associated with intrauterine growth restriction and pre-eclampsia |
title_short | Identification of placental nutrient transporters associated with intrauterine growth restriction and pre-eclampsia |
title_sort | identification of placental nutrient transporters associated with intrauterine growth restriction and pre-eclampsia |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833046/ https://www.ncbi.nlm.nih.gov/pubmed/29499643 http://dx.doi.org/10.1186/s12864-018-4518-z |
work_keys_str_mv | AT huangxiao identificationofplacentalnutrienttransportersassociatedwithintrauterinegrowthrestrictionandpreeclampsia AT anderlepascale identificationofplacentalnutrienttransportersassociatedwithintrauterinegrowthrestrictionandpreeclampsia AT hostettlerlu identificationofplacentalnutrienttransportersassociatedwithintrauterinegrowthrestrictionandpreeclampsia AT baumannmarcu identificationofplacentalnutrienttransportersassociatedwithintrauterinegrowthrestrictionandpreeclampsia AT surbekdanielv identificationofplacentalnutrienttransportersassociatedwithintrauterinegrowthrestrictionandpreeclampsia AT ontsoukaedgarc identificationofplacentalnutrienttransportersassociatedwithintrauterinegrowthrestrictionandpreeclampsia AT albrechtchristiane identificationofplacentalnutrienttransportersassociatedwithintrauterinegrowthrestrictionandpreeclampsia |