Expression profiling of endogenous secretory receptor for advanced glycation end products in human organs

Abstract

The receptor for advanced glycation end products (RAGE) is a cell surface multiligand receptor of the immunoglobulin superfamily, which participates in physiological and pathological processes such as neuronal development, diabetes, inflammation, neurodegenerative disorders, and cancer. A novel splice variant of RAGE-endogenous secretory decoy form (esRAGE) was recently identified and is thought to be a prospective candidate to modify these RAGE-associated conditions. Here, we investigated the expression and distribution of esRAGE and RAGE proteins with domain-specific antibodies. We studied a wide variety of adult normal human preparations obtained from surgical and autopsy specimens using a tissue microarray technique. The results revealed that esRAGE was widely distributed and we classified its expression into four patterns. In pattern A, the cytoplasm is stained diffusely in neurons, vascular endothelium, pneumocytes, mesothelium, pancreatic b cells, and macrophages/monocytes. In pattern B, dot-like granules are stained in the supranuclear regions facing the luminal surface of the bile ducts, salivary glands, digestive tracts, renal tubules, prostate, skin, thyroid, and bronchioles. Pattern C is represented by diffuse staining in the stromal area of the arterial walls. Pattern D shows diffuse and strong staining of secreted materials such as thyroidal colloid, crystals in renal tubular lumen, and glandular lumen in prostate. This study provides, for the first time, a histopathological basis for understanding the physiological roles of esRAGE in humans, and will contribute to elucidating the participation of esRAGE in pathological processes and to exploring novel diagnostic and therapeutic concepts.

Plasma Level of Endogenous Secretory RAGE Is Associated With Components of the Metabolic Syndrome and Atherosclerosis

“…All these findings strongly implicate RAGE signaling plays important roles in modulating local inflammation. Moreover, esRAGE is now shown to be expressed in wide variety of human tissues including vascular endothelium, pneumocytes, pancreatic beta cells, monocyte/macrophages, and various epithelial cells, 45 many cells of which play pivotal roles in local inflammation. Even though the origin of cells determining plasma esRAGE is not clear, the association of plasma esRAGE with components of metabolic syndrome or atherosclerosis may be linked to inflammation-modulatory roles of esRAGE.…”

AGE/RAGE as a Mediator of Insulin Resistance or Metabolic Syndrome: Another Aspect of Metabolic Memory?

“…A tissue microarray technique using a wide variety of adult normal human preparations obtained from surgical and autopsy specimens revealed that esRAGE was widely distributed in tissues, including vascular endothelium, monocyte/macrophage, pneumocytes, and several endocrine organs 141 . However, it is unclear at present from which organ or tissue plasma sRAGE or esRAGE originate.…”

Pharmacokinetics and lung distribution of a humanized anti-RAGE antibody in wild-type and RAGE-/-mice

“…3,4,6 In healthy animals and humans, RAGE expression is most prominent in the lung, including alveolar type I and type II epithelial cells, alveolar macrophage, endothelia and some bronchiolar epithelia. [7][8][9][10] The activation of RAGE by its ligands triggers several signal transduction pathways involved in acute and chronic inflammation, including the NFκB and MAP kinase pathway. 1,11,12 In turn, NFκB upregulates RAGE expression, leading to the amplification of the pro-inflammatory cascade.…”