Receptors for Advanced Glycation End‐Products (RAGE) are Transcriptionally Inhibited by FoxA2 in Diverse Pulmonary Cell Types

Abstract

The receptor for advanced glycation end‐products (RAGE) has been developmentally identified on the membranes of ATI cells and has been implicated in the spreading and adherence that characterize the transitioning of ATII cells to ATI cells. We have previously demonstrated that TTF‐1 and Egr‐1, transcriptional regulators that function during lung development, regulate RAGE transcription. However, the precise pattern of transcription factors that limit RAGE expression to pulmonary‐specific cell types remained unclear. In the current study, transcriptional regulation of RAGE was assessed by transfection of ATII‐like alveolar epithelium (A‐549), bronchiolar epithelium (Beas2B), and macrophages (RAW 264.7) with a luciferase reporter containing 0.9‐kb of the mouse RAGE promoter. In addition to the reporter construct, each cell type was transfected with FoxA2, a winged double helix DNA binding protein that influences respiratory epithelial cell differentiation. In each case, FoxA2 repressed RAGE transcription in vitro. Mutagenesis of a proximal promoter region revealed that FoxA2 directly interacts with the coding sequence for RAGE. These data show that FoxA2 may negatively regulate RAGE expression by respiratory epithelium during pulmonary development. This work was supported by a grant from the Flight Attendant's Medical Research Institute (FAMRI, PRR) and a BYU Mentoring Environment Grant (PRR).