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Receptor for advanced glycation end products (RAGE) knockout reduces fetal dysmorphogenesis in murine diabetic
Andreas Ejdesjö1, Sebastian Brings2, Thomas Fleming2
1Department of Medical Cell Biology, Medical Faculty of Uppsala University, Biomedical Centre, P.O. Box 751, SE-75123 Uppsala, Sweden.
Abstract:
The receptor for Advanced Glycation End products (RAGE) is implicated in the pathogenesis of diabetic complications, but its importance in diabetic embryopathy is unclear. We therefore investigated the role of RAGE in diabetic embryopathy using streptozotocin induced diabetes in female wild type (WT) C57Bl/6N and RAGE knockout C57Bl/6N (RAGE(-/-)) mice, mated with control males of the same genotype. Maternal diabetes induced more fetal resorption and malformation (facial skeleton, neural tube) in the WT than in the RAGE(-/-) fetuses. Maternal plasma glucose and methylgyoxal concentrations, as well as embryonic N(ε)-carboxymethyl-lysine (CML) levels were increased to the same extent in diabetic WT and RAGE(-/-) pregnancy. However, maternal diabetes induced increased fetal hepatic isoprostane 8-iso-PGF2α levels (oxidative stress marker) and embryonic activation of NFκB in WT only (not in RAGE(-/-) embryos). The association between RAGE knockout and diminished embryonic dysmorphogenesis in diabetic pregnancy suggests that embryonic RAGE activation is involved in diabetic embryopathy.
Insights
Diabetic embryopathy, or birth defects in infants of diabetic mothers, is reduced when the receptor for Advanced Glycation End products (RAGE) is absent. Embryonic RAGE activation contributes to these developmental issues.
Area of Science:
- Reproductive biology
- Developmental biology
- Endocrinology
Background:
- The receptor for Advanced Glycation End products (RAGE) is linked to diabetic complications.
- The specific role of RAGE in diabetic embryopathy remains largely unknown.
- Diabetic embryopathy presents significant risks for fetal development.
Purpose of the Study:
- To investigate the role of RAGE in the pathogenesis of diabetic embryopathy.
- To determine if embryonic RAGE activation contributes to malformations in diabetic pregnancies.
Main Methods:
- Utilized streptozotocin-induced diabetes in wild-type (WT) and RAGE knockout (RAGE(-/-)) female mice.
- Assessed fetal resorption and malformation rates in offspring of diabetic and control mice.
- Measured maternal glucose, methylglyoxal, embryonic CML, fetal hepatic isoprostane, and embryonic NFκB activation.
Main Results:
- Maternal diabetes caused increased fetal resorption and malformations in WT but not RAGE(-/-) fetuses.
- Elevated maternal glucose, methylglyoxal, and embryonic CML levels were similar in diabetic WT and RAGE(-/-) pregnancies.
- Maternal diabetes increased fetal oxidative stress (isoprostane) and embryonic NFκB activation in WT but not RAGE(-/-) embryos.
Conclusions:
- Embryonic RAGE activation is implicated in the development of diabetic embryopathy.
- Targeting embryonic RAGE may offer a strategy to prevent birth defects in diabetic pregnancies.
