Differential Placental Expression of the Receptor for Advanced Glycation End‐Products (RAGE) in Normal and Complicated Pregnancies

Abstract

Receptor for Advanced Glycation End‐Products (RAGE) is a cell surface receptor that modulates inflammatory pathways. Inflammation is associated with the development of pregnancy pathologies such as preeclampsia (PE), intrauterine growth restriction (IUGR), gestational diabetes mellitus (GDM), and pre‐term labor (PTL) that can lead to maternal and fetal complications. Our objective was to examine placental RAGE expression to implicate RAGE signaling in these complications. We performed qPCR, western blotting and immunofluorescence to determine levels of RAGE gene activation, protein expression and RAGE localization in the placenta. An ELISA was used to determine TNF‐α secretion. First trimester trophoblast cells were used to examine RAGE expression and downstream signaling molecules after RAGE activation by the ligand AGEs. Compared to control placental samples we observed: 1) increased localization of RAGE to the PE placental trophoblast; 2) decreased RAGE localization in the IUGR placenta; 3) a 1.5 fold increase (p<0.05) in placental RAGE gene expression during IUGR; 3) a 2‐fold increase (p<0.03) of placental RAGE protein expression in PE/IUGR; and 3) a 2‐fold decrease (p<0.05) in placental RAGE protein expression during IUGR. In first trimester cell lines we observed: 1) an 8‐fold increase in p‐ERK expression after 25ug treatment of AGES (p<0.007) and 2) a 1.8‐fold increase (p<0.05) of TNF‐α secretion after 25ug treatment of AGEs, a common RAGE ligand. We conclude that placental RAGE is activated in PE/IUGR situations and that RAGE‐mediated inflammation in the trophoblast includes increased TNF‐α secretion through the activation of ERK signaling.