The Receptor for Advanced Glycation End Products Is Induced by the Glycation Products Themselves and Tumor Necrosis Factor-α through Nuclear Factor-κB, and by 17β-Estradiol through Sp-1 in Human Vascular Endothelial Cells

Abstract

The binding of advanced glycation end products (AGE) to the receptor for AGE (RAGE) is known to deteriorate various cell functions and is implicated in the pathogenesis of diabetic vascular complications. Here we show that AGE, tumor necrosis factor-␣ (TNF-␣), and 17␤-estradiol (E 2 ) up-regulated RAGE mRNA and protein levels in human microvascular endothelial cells and ECV304 cells, with the mRNA stability being essentially invariant. Transient transfection experiments with human RAGE promoter-luciferase chimeras revealed that the region from nucleotide number ؊751 to ؊629 and the region from ؊239 to ؊89 in the RAGE 5-flanking sequence exhibited the AGE/TNF-␣ and E 2 responsiveness, respectively. Site-directed mutation of an nuclear factor-B (NF-B) site at ؊671 or of Sp-1 sites at ؊189 and ؊172 residing in those regions resulted in an abrogation of the AGE/TNF-␣-or E 2 -mediated transcriptional activation. Electrophoretic mobility shift assays revealed that ECV304 cell nuclear extracts contained factors which retarded the NF-B and Sp-1 elements, and that the DNA-protein complexes were supershifted by antip65/p50 NF-B and anti-Sp-1/estrogen receptor ␣ antibodies, respectively. These results suggest that AGE, TNF-␣, and E 2 can activate the RAGE gene through NF-B and Sp-1, causing enhanced AGE-RAGE interactions, which would lead to an exacerbation of diabetic microvasculopathy.

Articular chondrocytes express the receptor for advanced glycation end products: Potential role in osteoarthritis

“…Our findings would be consistent with this, since AGEs are present at much higher levels in cartilage from older adults (39,40), and other RAGE ligands, including S100A4 (41) and HMGB-1 (11), appear to be increased in OA cartilage. The RAGE promoter has been found to contain NF-B binding sites (29), and expression of RAGE is increased by RAGE ligands and inflammatory mediators including TNF␣ (35,42). We found that fibronectin fragments and IL-1␤, which have both been found in cartilage and synovial fluid from patients with OA and RA (30,43), can stimulate chondrocyte RAGE expression.…”

“…Polyclonal (AB5484) and monoclonal (MAB5328) antibodies to RAGE were purchased from Chemicon (Temecula, CA). The immunogen for the polyclonal antibody was a synthetic peptide corresponding to amino acids [42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59] in the N-terminal domain of RAGE, whereas the monoclonal antibody was raised against a recombinant protein containing the extracellular domains of RAGE. A third anti-RAGE antibody (C-20; Santa Cruz Biotechnology, Santa Cruz, CA) was used, and the immunogen was a synthetic peptide corresponding to a region in the carboxy-terminus of RAGE.…”

The Mechanisms of Inhibition of Advanced Glycation End Products Formation through Polyphenols in Hyperglycemic Condition

“…Hyperglycemia stimulates an excessive expression of RAGE on pericytes and endothelial cells which results in a deterioration of pericytes. Loss of pericytes leads to vascular damage and clinical expression of retinopathy [27,28]. Moreover, a high level of AGEs in retinal cells induces expression of vascular endothelial growth factor which causes destruction of the blood-retinal barrier and microvascular hyper-permeability, which finally leads to blindness or poorness of vision [29].…”

Anti–tumor necrosis factor α therapy in fifteen patients with AA amyloidosis secondary to inflammatory arthritides: A followup report of tolerability and efficacy

“…In addition, recombinant TNF enhances amyloid deposition in the Syrian hamster (10). Furthermore, TNF favors the expression of receptors for advanced glycation end products (11), whose interaction with amyloid fibrils is responsible for cytotoxicity and tissue damage (12). Thus, TNF-blocking agents might not only reduce the synthesis of amyloid precursors but also slow amyloid deposition and thus attenuate the consequences of the interaction between amyloid fibrils and their receptors in the cells and tissues (Figure 2).…”