The receptor for advanced glycation end products (RAGE) and the lung

Abstract

The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell surface molecules. As a pattern-recognition receptor capable of binding a diverse range of ligands, it is typically expressed at low levels under normal physiological conditions in the majority of tissues. In contrast, the lung exhibits high basal level expression of RAGE localised primarily in alveolar type I (ATI) cells, suggesting a potentially important role for the receptor in maintaining lung homeostasis. Indeed, disruption of RAGE levels has been implicated in the pathogenesis of a variety of pulmonary disorders including cancer and fibrosis. Furthermore, its soluble isoforms, sRAGE, which act as decoy receptors, have been shown to be a useful marker of ATI cell injury. Whilst RAGE undoubtedly plays an important role in the biology of the lung, it remains unclear as to the exact nature of this contribution under both physiological and pathological conditions.

Figure 1

Schematic representation of RAGE and the generation of some of its isoforms commonly found in the lung. In addition to its full-length form (mRAGE), RAGE also exists in a soluble form (sRAGE) which lacks the transmembrane and cytosolic domains found in mRAGE. Production of sRAGE isoforms is via either proteolytic cleavage, which gives rise to cleaved RAGE (cRAGE) or alternative splicing at exon 9 resulting in a C-truncated form termed endogenous secretory RAGE (esRAGE).

Figure 2

Tissue distribution of RAGE. (a) Relative number of expressed-sequence clones per million identified in tissue and species-specific databases [11]. The table was updated on 07/20/09. (b) Quantitative analysis of RAGE mRNA expression in healthy human tissue. Two sets of RAGE-specific primers, RAqu_2 (black) and RAqu_3 (white), were used to compare RAGE expression in 16 human tissues of healthy donors in quantitative RT-PCR analysis. The transcript numbers of RAGE were compared with the transcript numbers of GAPDH in 2 μL cDNA. The mean and SEM of two separate light cycler runs are displayed (adapted from [12]).

Figure 3

RAGE is central to many fundamental biological processes in the lung. Expression of RAGE has been shown to promote spreading of adherent cells on collagen IV and in doing so may ensure effective gas exchange. RAGE-expressing epithelial cells exhibit diminished proliferative capacity compared to non-expressing cells. Cells overexpressing RAGE adhere much faster to collagen IV, and to a greater extent when compared to mock transfected cells suggesting an important role in cell-extracellular matrix interactions.