RAGE: developmental expression and positive feedback regulation by Egr-1 during cigarette smoke exposure in pulmonary epithelial cells

Abstract

The receptor for advanced glycation end-products (RAGE) is a member of the immunoglobin superfamily of multiligand receptors. Following ligand binding, mechanisms associated with host defense, tissue remodeling, and inflammation are activated. RAGE is highly expressed in pulmonary epithelium transitioning from alveolar type (AT) II to ATI cells and is upregulated in the presence of ligand; however, the regulation and function of RAGE during development are less clear. Herein, immunohistochemistry demonstrated a temporal-spatial pattern of RAGE expression in pulmonary epithelial cells from embryonic day 17.5 to postnatal day 10. Cotransfection experiments revealed that the mouse RAGE promoter was activated by early growth response gene 1 (Egr-1) and inhibited by thyroid transcription factor-1 (TTF-1) via interaction with specific regulatory elements. A rat ATI cell line (R3/1) with endogenous RAGE expression also differentially regulated RAGE when transfected with TTF-1 or Egr-1. Because Egr-1 is markedly induced in pulmonary epithelial cells exposed to cigarette smoke extract (CSE; Reynolds PR, Hoidal JR. Am J Respir Cell Mol Biol 35: 314 -319, 2006.), we sought to investigate RAGE induction by CSE. Employing RT-PCR and Western blotting, RAGE and common ligands (amphoterin and S100A12) were upregulated in epithelial (R3/1 and A549) and macrophage (RAW) cell lines following exposure to CSE. Immunostaining for RAGE in cells similarly exposed and in lungs from mice exposed to cigarette smoke for 6 mo revealed elevated RAGE expression in pulmonary epithelium. After the addition of glyoxylated BSA, an advanced glycation end-product that binds RAGE, real-time RT-PCR detected a 200-fold increase in Egr-1. These results indicate that Egr-1 regulates RAGE expression during development and the likelihood of positive feedback involving Egr-1 and RAGE in cigarette smokerelated disease.

Transient early wheeze and lung function in early childhood associated with chronic obstructive pulmonary disease genes

“…34 RAGE expression is most abundant in the lung, and the intensity of expression in respiratory epithelial cells varies during lung morphogenesis. 35 It has been shown to play a role in critical processes directly involved in perinatal transitioning of the embryonic lung into a mature functional organ. 35 Hedgehog-interacting protein (HHIP) has been implicated in organ development and repair in multiple tissues 36 and is therefore a strong candidate gene for COPD.…”

“…35 It has been shown to play a role in critical processes directly involved in perinatal transitioning of the embryonic lung into a mature functional organ. 35 Hedgehog-interacting protein (HHIP) has been implicated in organ development and repair in multiple tissues 36 and is therefore a strong candidate gene for COPD. Our findings of HHIP SNP rs1828591 risk alleles being associated with an increased risk of TEW and lower lung function support our hypothesis.…”

Serum soluble receptor for advanced glycation end products (sRAGE) is independently associated with cigarette smoking in non-diabetic healthy subjects

“…1 The lung tissue is directly exposed to cigarette smoke in smokers, and the cigarette smoke has been shown to elevate RAGE expression in cultured cells and in the lung tissues of animals. 2 Some of the diseases prevalent among cigarette smokers, particularly atherosclerotic cardiovascular diseases and cancer, have also been shown to be linked with RAGE signalling. 3 A soluble form of RAGE (sRAGE), which is a splice variant of full-length RAGE or a shedding/cleavage product of membrane-bound RAGE, has been found circulating in the plasma.…”

Combined effects of maternal inflammation and neonatal hyperoxia on lung fibrosis and RAGE expression in newborn rats

“…The RAGE proteins are expressed at low to undetectable levels in most tissues but are most abundant in the lung (10). High levels of RAGE expression during periods of lung development suggest functionality in lung morphogenesis (11). The effect of hyperoxia on RAGE expression has been shown to differ between adult mouse and neonatal rat models (12,13).…”