Activation of the receptor for advanced glycation end products triggers a p21(ras)-dependent mitogen-activated protein kinase pathway regulated by oxidant stress.

Harry M Lander,Osamu Hori,Rebecca A Moss,Ann Marie Schmidt,Jason S Ogiste,James M Tauras

doi:10.1074/jbc.272.28.17810

Abstract

Advanced glycation end products (AGEs) exert their cellular effects on cells by interacting with specific cellular receptors, the best characterized of which is the receptor for AGE (RAGE). The transductional processes by which RAGE ligation transmits signals to the nuclei of cells is unknown and was investigated. AGE-albumin, a prototypic ligand, activated p21(ras) in rat pulmonary artery smooth muscle cells that express RAGE, whereas nonglycated albumin was without effect. MAP kinase activity was enhanced at concentrations of AGE-albumin, which activated p21(ras) and NF-kappaB. Depletion of intracellular glutathione rendered cells more sensitive to AGE-mediated activation of this signaling pathway. In contrast, signaling was blocked by preventing p21(ras) from associating with the plasma membrane or mutating Cys118 on p21(ras) to Ser. Signaling was receptor-dependent, because it was prevented by blocking access to RAGE with either anti-RAGE IgG or by excess soluble RAGE. These data suggest that RAGE-mediated induction of cellular oxidant stress triggers a cascade of intracellular signals involving p21(ras) and MAP kinase, culminating in transcription factor activation. The molecular mechanism that triggers this pathway likely involves oxidant modification and activation of p21(ras).

Highlights

Advanced glycation end products (AGEs) exert their cellular effects on cells by interacting with specific cellular receptors, the best characterized of which is the receptor for AGE (RAGE)
Given the enhanced expression of AGE and RAGE in diabetic vascular smooth muscle, we focused on elucidating the signaling pathways in smooth muscle cells that are triggered upon ligation of RAGE by AGE-albumin, a prototypical ligand
We have previously demonstrated that this concentration of AGE-albumin was optimal for AGE-RAGE-mediated cellular oxidant stress [12]

Summary

Introduction

Advanced glycation end products (AGEs) exert their cellular effects on cells by interacting with specific cellular receptors, the best characterized of which is the receptor for AGE (RAGE). AGE-albumin, a prototypic ligand, activated p21ras in rat pulmonary artery smooth muscle cells that express RAGE, whereas nonglycated albumin was without effect. Signaling was receptor-dependent, because it was prevented by blocking access to RAGE with either anti-RAGE IgG or by excess soluble RAGE These data suggest that RAGE-mediated induction of cellular oxidant stress triggers a cascade of intracellular signals involving p21ras and MAP kinase, culminating in transcription factor activation. We have recently demonstrated the enhanced presence of RAGE in vascular smooth muscle of diabetic vasculature (renal arterial vessel) compared. Given the enhanced expression of AGE and RAGE in diabetic vascular smooth muscle, we focused on elucidating the signaling pathways in smooth muscle cells that are triggered upon ligation of RAGE by AGE-albumin, a prototypical ligand. Others have found that induction of c-fos expression by tumor necrosis factor-␣ and basic fibroblast growth factor requires production of reactive oxygen intermediates [16], as does activation of the MAP kinase cascade in NIH-3T3 cells [17] and in neutrophils [18]

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