Increased Rat Placental Fatty Acid, but Decreased Amino Acid and Glucose Transporters Potentially Modify Intrauterine Programming

Nüsken, Eva; Gellhaus, Alexandra; Kühnel, Elisabeth; Swoboda, Isabelle; Wohlfarth, Maria; Vohlen, Christina; Schneider, Holm; Dötsch, Jörg; Nüsken, Kai-Dietrich

doi:10.1002/jcb.25450

Cited by 16 publications

(13 citation statements)

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“…A study using the vessel ligation model showed that the expression of GLUT1 transporters and Cx26 channels is downregulated in rat placentas at term (Nüsken et al, 2016 ), a finding that confirms the results of Das et al ( 1998 ), who used a similar ligation model and found a downregulation in placental GLUT1 protein expression and reduced fetal glucose uptake. Therefore, regulation of GLUT1 seems to be downregulated if both nutrition and oxygen levels are strongly reduced.…”

Section: Comparison Of Placental Transport Mechanisms Of Rodents and supporting

confidence: 69%

“…Interestingly, Nüsken et al ( 2016 ), using a bilateral uterine artery and vein ligation rat model that limits both oxygen and nutrient delivery to the fetus, found a downregulation of the neutral amino acid transporters SNAT1 and SNAT2, combined with growth-restricted pups exhibiting a phenotype similar to that of the low-protein model. However, this study also found that sham-operated rats exhibited reduced amino acid transporter expression and reductions in the body weight of the pups.…”

Section: Comparison Of Placental Transport Mechanisms Of Rodents and mentioning

confidence: 99%

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Transplacental Nutrient Transport Mechanisms of Intrauterine Growth Restriction in Rodent Models and Humans

Winterhager

Gellhaus

2017

Front. Physiol.

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Although the causes of intrauterine growth restriction (IUGR) have been intensively investigated, important information is still lacking about the role of the placenta as a link from adverse maternal environment to adverse pregnancy outcomes of IUGR and preterm birth. IUGR is associated with an increased risk of cardiovascular, metabolic, and neurological diseases later in life. Determination of the most important pathways that regulate transplacental transport systems is necessary for identifying marker genes as diagnostic tools and for developing drugs that target the molecular pathways. Besides oxygen, the main nutrients required for appropriate fetal development and growth are glucose, amino acids, and fatty acids. Dysfunction in transplacental transport is caused by impairments in both placental morphology and blood flow, as well as by factors such as alterations in the expression of insulin-like growth factors and changes in the mTOR signaling pathway leading to a change in nutrient transport. Animal models are important tools for systematically studying such complex events. Debate centers on whether the rodent placenta is an appropriate tool for investigating the alterations in the human placenta that result in IUGR. This review provides an overview of the alterations in expression and activity of nutrient transporters and alterations in signaling associated with IUGR and compares these findings in rodents and humans. In general, the data obtained by studies of the various types of rodent and human nutrient transporters are similar. However, direct comparison is complicated by the fact that the results of such studies are controversial even within the same species, making the interpretation of the results challenging. This difficulty could be due to the absence of guidelines of the experimental design and, especially in humans, the use of trophoblast cell culture studies instead of clinical trials. Nonetheless, developing new therapy concepts for IUGR will require the use of animal models for gathering robust data about mechanisms leading to IUGR and for testing the effectiveness and safety of the intervention among pregnant women.

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Section: Comparison Of Placental Transport Mechanisms Of Rodents and supporting

confidence: 69%

Section: Comparison Of Placental Transport Mechanisms Of Rodents and mentioning

confidence: 99%

Transplacental Nutrient Transport Mechanisms of Intrauterine Growth Restriction in Rodent Models and Humans

Winterhager

Gellhaus

2017

Front. Physiol.

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“…Functionally, placentas from protein-restricted rodents are known to differ in terms of materno-fetal steroid exchange [ 11 ] and transport of fatty acids and amino acids [ 12 , 25 , 26 ]. Whilst specific genes related to these functions have been previously identified as being sensitive to protein restriction, none were found to be differentially expressed in the current study.…”

Section: Discussionmentioning

confidence: 99%

The effect of maternal undernutrition on the rat placental transcriptome: protein restriction up-regulates cholesterol transport

et al. 2016

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BackgroundFetal exposure to a maternal low protein diet during rat pregnancy is associated with hypertension, renal dysfunction and metabolic disturbance in adult life. These effects are present when dietary manipulations target only the first half of pregnancy. It was hypothesised that early gestation protein restriction would impact upon placental gene expression and that this may give clues to the mechanism which links maternal diet to later consequences.MethodsPregnant rats were fed control or a low protein diet from conception to day 13 gestation. Placentas were collected and RNA sequencing performed using the Illumina platform.ResultsProtein restriction down-regulated 67 genes and up-regulated 24 genes in the placenta. Ingenuity pathway analysis showed significant enrichment in pathways related to cholesterol and lipoprotein transport and metabolism, including atherosclerosis signalling, clathrin-mediated endocytosis, LXR/RXR and FXR/RXR activation. Genes at the centre of these processes included the apolipoproteins ApoB, ApoA2 and ApoC2, microsomal triglyceride transfer protein (Mttp), the clathrin-endocytosis receptor cubilin, the transcription factor retinol binding protein 4 (Rbp4) and transerythrin (Ttr; a retinol and thyroid hormone transporter). Real-time PCR measurements largely confirmed the findings of RNASeq and indicated that the impact of protein restriction was often striking (cubilin up-regulated 32-fold, apoC2 up-regulated 17.6-fold). The findings show that gene expression in specific pathways is modulated by maternal protein restriction in the day-13 rat placenta.ConclusionsChanges in cholesterol transport may contribute to altered tissue development in the fetus and hence programme risk of disease in later life.Electronic supplementary materialThe online version of this article (doi:10.1186/s12263-016-0541-3) contains supplementary material, which is available to authorized users.

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“…For protein detection, a total of 20 μg was separated on 8%, 12%, and 14.5% polyacrylamide gels and electrophoretically transferred to nitrocellulose membranes for 120 min at 70 mA per membrane (Hybond‐C Extra; Amersham Biosciences, Freiburg, Germany). Membranes were blocked for 1 h with 5% non‐fat dried milk in Tris‐buffered saline containing 0.15% (v/v) Tween20 (Sigma–Aldrich), followed by incubation overnight with primary antibodies in blocking buffer at 4°C, such as IGF2 (rabbit anti‐mouse, ab9574; Abcam, Cambridge, UK), CD31 (rat anti‐mouse, DIA 310, Dianova, Hamburg, Germany), ABCA1 (rabbit anti‐mouse, ab 7360; Abcam), Cx26 (rabbit anti‐Cx26, bs‐1715R, BIOSS, Woburn, MA), h‐FABP (rabbit anti‐cardiac FABP, ab133585, Abcam), CD36 (mouse anti‐CD36, NB110‐59724, Novus Biologicals, Littleton, CO), SNAT2 (rabbit‐anti‐SNAT2, H‐60, sc‐67081, Santa Cruz Biotechnology), SNAT1 (mouse anti‐SNAT1, sc‐137032, Santa Cruz Biotechnology) and GLUT‐1 (rabbit anti‐GLUT‐1,NB110‐39113, Novus Biologicals, Littleton, CO) as described previously in Nüsken et al [].…”

Section: Methodsmentioning

confidence: 99%

Placental‐Specific Overexpression of sFlt‐1 Alters Trophoblast Differentiation and Nutrient Transporter Expression in an IUGR Mouse Model

Kühnel

Kleff

Stojanovska

et al. 2017

J of Cellular Biochemistry

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Since it is known that placental overexpression of the human anti-angiogenic molecule sFlt-1, the main candidate in the progression of preeclampsia, lead to intrauterine growth restriction (IUGR) in mice by lentiviral transduction of mouse blastocysts, we hypothesize that sFlt-1 influence placental morphology and physiology resulting in fetal IUGR. We therefore examined the effect of sFlt-1 on placental morphology and physiology at embryonic day 18.5 with histologic and morphometric analyses, transcript analyses, immunoblotting, and methylation studies. Interestingly, placental overexpression of sFlt-1 leads to IUGR in the fetus and results in lower placental weights. Moreover, we observed altered trophoblast differentiation with reduced expression of IGF2, resulting in a smaller placenta, a smaller labyrinth, and the loss of glycogen cells in the junctional zone. Changes in IGF2 are accompanied by small changes in its DNA methylation, whereas overall DNA methylation is unaffected. In addition, the expression of placental nutrient transporters, such as the glucose diffusion channel Cx26, is decreased. In contrast, the expression of the fatty acid transporter CD36 and the cholesterol transporter ABCA1 is significantly increased. In conclusion, placental sFlt-1 overexpression resulted in a reduction in the differentiation of the spongiotrophoblast into glycogen cells. These findings of a reduced exchange area of the labyrinth and glycogen stores, as well as decreased expression of glucose transporter, could contribute to the intrauterine growth restriction phenotype. All of these factors change the intrauterine availability of nutrients. Thus, we speculate that the alterations triggered by increased anti-angiogenesis strongly affect fetal outcome and programming. J. Cell. Biochem. 118: 1316-1329, 2017. © 2016 Wiley Periodicals, Inc.

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Increased Rat Placental Fatty Acid, but Decreased Amino Acid and Glucose Transporters Potentially Modify Intrauterine Programming

Cited by 16 publications

References 50 publications

Transplacental Nutrient Transport Mechanisms of Intrauterine Growth Restriction in Rodent Models and Humans

Transplacental Nutrient Transport Mechanisms of Intrauterine Growth Restriction in Rodent Models and Humans

The effect of maternal undernutrition on the rat placental transcriptome: protein restriction up-regulates cholesterol transport

Placental‐Specific Overexpression of sFlt‐1 Alters Trophoblast Differentiation and Nutrient Transporter Expression in an IUGR Mouse Model

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