Embryonic Mice with Lung-Specific RAGE Upregulation Have Enhanced Mitochondrial Respiration

Abstract

RAGE (receptor for advanced glycation end-products) represents a class of multi-ligand pattern recognition receptors highly expressed in the vertebrate lung. Our previous work demonstrated unique patterns of RAGE expression in the developing murine lung and regulation by key transcription factors including NKX2.1 and FoxA2. The current investigation employed conditional lung-specific upregulation via a TetOn transgenic mouse model (RAGE TG) and nontransgenic controls. RAGE expression was induced in RAGE TG mice throughout gestation (embryonic day, E0-E18.5) or from E15.5-E18.5 and compared to age-matched controls. High-resolution respirometry was used to assess mitochondrial respiration and context was provided by quantifying ATP and reactive oxygen species (ROS) generation. Lung lysates were also screened by immunoblotting for MAPK/PI3K signaling intermediates. RAGE upregulation increased mitochondrial oxygen consumption in the E0-E18.5 and E15.5-E18.5 groups compared to controls. RAGE TG mice also had increased ATP concentrations, which persisted even after controlling for oxygen consumption. In contrast, ROS generation was diminished in RAGE TG animals compared to controls. Lastly, in both RAGE TG groups, pERK and pp38 were significantly decreased, whereas pAKT was significantly elevated, suggesting that RAGE signaling is likely perpetuated via pAKT pathways. Together, these data demonstrate that despite lung hypoplasia in RAGE TG mice, the remaining tissue experiences a favorable shift in mitochondrial bioenergetics without excessive redox assault and a preference for AKT signaling over ERK or p38.