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Receptor for Advanced Glycation End products (RAGE) knockout reduces fetal dysmorphogenesis in murine diabetic pregnancy
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. (Teratology)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
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2016 (English)In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 62, 62-70 p.Article in journal (Other academic) Published
Abstract [en]

Background & Aim: The receptor for Advanced Glycation End products (RAGE) is implicated in the pathogenesis of diabetic complications, but its importance for the induction of congenital malformations in diabetic pregnancy is unclear. The aim of the present study was to investigate a possible role of RAGE activation in the induction of diabetic embryopathy.

Methods: Female non-diabetic and diabetic wildtype (WT) C57Bl/6 mice and RAGE knockout C57Bl/6 (RAGE‑/-) mice were mated with males of the same genotype. Diabetes was induced by daily streptozotocin (STZ) injections (50 mg/kg STZ i.p.) on five consecutive days. On gestational day 18, pregnant mice were anesthetized and blood was drawn from the heart to measure maternal metabolic parameters. Fetuses and placentas were excised, weighed, and examined for morphological anomalies, and fetal livers were analyzed for 8‑iso‑PGF levels.

Results: There were no malformations in non-diabetic WT or non-diabetic RAGE‑/- mice. However, resorption rates were higher in non-diabetic WT (10%) than in non-diabetic RAGE‑/- mice (4%). Diabetic WT mice had higher malformation (22%) and resorption (43%) rates than diabetic RAGE‑/- mice (3% malformations and 21% resorptions). Maternal diabetes decreased fetal weight more in WT fetuses (44%) than in RAGE‑/- fetuses (36%). There were no differences in plasma glucose levels between the diabetic WT and RAGE‑/- mice, but plasma levels of triglycerides and cholesterol were lower in diabetic WT mice than in diabetic RAGE-/- mice. Diabetes increased maternal plasma levels of methylglyoxal in WT and RAGE‑/- mice, and increased fetal hepatic levels of 8-iso-PGF in WT fetuses, but not in RAGE‑/- fetuses.

Discussion: Knockout of RAGE diminished the rates of fetal malformations and resorptions, despite similar levels of hyperglycemia in pregnant diabetic mice. An anti-teratogenic effect was present in RAGE‑/- mice despite having a more severe diabetic state than diabetic WT mice. As 8-iso-PGF, a marker of oxidative stress, only increased in diabetic WT offspring, this suggested a pivotal role of RAGE activation and oxidative stress in the pathogenesis of diabetic embryopathy.

Place, publisher, year, edition, pages
2016. Vol. 62, 62-70 p.
Keyword [en]
Diabetes; AGE; RAGE; Oxidative stress; Diabetic embryopathy; Neural tube defects; Experimental teratology
National Category
Cell and Molecular Biology
Research subject
Medical Cell Biology
URN: urn:nbn:se:uu:diva-178170DOI: 10.1016/j.reprotox.2016.04.015ISI: 000378367700008PubMedID: 27109771OAI: oai:DiVA.org:uu-178170DiVA: diva2:542211
Swedish Diabetes AssociationNovo NordiskSwedish Research Council, 54X-21117German Research Foundation (DFG), SFB1118
Available from: 2012-07-30 Created: 2012-07-30 Last updated: 2016-07-27Bibliographically approved
In thesis
1. Teratogenic Predisposition in Diabetic Rat Pregnancy
Open this publication in new window or tab >>Teratogenic Predisposition in Diabetic Rat Pregnancy
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Pre-gestational diabetes increases the risk of congenital malformation in the offspring and both morbidity and mortality in the diabetic mother and her offspring. During pregnancy, high glucose levels act as a teratogen through several cellular and biochemical pathways and increased production of reactive oxygen species (ROS) has a central role in diabetic embryopathy. The aim of this work was to investigate the importance of genetic predisposition for congenital malformations and to study the genes involved in the teratogenic process of diabetic pregnancy.

The crossbreeding of two rat strains, with both low and high incidence of diabetes-induced malformations, indicated that strain-specific maternal factors, such as disturbed serum levels of amino acids, triglycerides, and β-hydroxybutyrate, were associated with malformation. In addition, disturbed fetal expression of genes involved in ROS defense and development (Shh, Bmp4, Ret and Gdnf) in mandible and heart, and decreased activity of Gapdh and Aldose Reductase were associated with the teratogenic process, and the trans-generational heredity of the mother determined the type of malformations induced by maternal diabetes.

In rat embryos, a diabetic environment in utero changed the expression of genes involved in ROS defense (Nrf2, Gpx1 and Cat), development of mandible and heart (Msx2, Shh, Bmp4, Ret and Gdnf), and neural tube closure and apoptosis (Pax3 and p53). The changes were divergent with tissue-specific alterations of gene expression in developing mandible, heart anlage, and whole embryo.

Disruption of the Receptor for Advanced Glycation End products (RAGE) had a protective effect against diabetic embryopathy in mice, and the blockage of RAGE diminished ROS production in the offspring: this supported oxidative stress being a necessary etiological component in diabetic embryopathy.

Maternal metabolic state and genetic susceptibility influence fetal outcome in experimental diabetic pregnancy. Disturbed protection against oxidative stress and tissue-specific derangements in the expression of developmental genes play pivotal roles in the teratogenic mechanism, and enhanced levels of Advanced Glycation End products (AGE) and RAGE-induced oxidative stress are involved in diabetic dysmorphogenesis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 78 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 797
diabetes, malformations, teratogenic, advanced glycation end products, AGE, RAGE, oxidative stress, ROS, gene expression
National Category
Cell and Molecular Biology
Research subject
Medical Cell Biology
urn:nbn:se:uu:diva-178175 (URN)978-91-554-8434-7 (ISBN)
Public defence
2012-09-28, A1:107a, Biomedical Centre, Husargatan 3, Uppsala, 09:15 (English)
Available from: 2012-09-07 Created: 2012-07-30 Last updated: 2013-01-22Bibliographically approved

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Ejdesjö, AndreasFred, Rikard G.Eriksson, Ulf J
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