Receptor-mediated endothelial cell dysfunction in diabetic vasculopathy. Soluble receptor for advanced glycation end products blocks hyperpermeability in diabetic rats.

Abstract

Dysfunctional endothelium is associated with and, likely, predates clinical complications of diabetes mellitus, by promoting increased vascular permeability and thrombogenicity. Irreversible advanced glycation end products (AGEs), resulting from nonenzymatic glycation and oxidation of proteins or lipids, are found in plasma, vessel wall, and tissues and have been linked to the development of diabetic complications. The principal means through which AGEs exert their cellular effects is via specific cellular receptors, one of which, receptor for AGE (RAGE), is expressed by endothelium. We report that blockade of RAGE inhibits AGE-induced impairment of endothelial barrier function, and reverses, in large part, the early vascular hyperpermeability observed in diabetic rats. Inhibition of AGE-and dia- IntroductionExposure of proteins or lipids to reducing sugars results in nonenzymatic glycation and oxidation. Initially, reversible early glycation adducts, Schiff bases and Amadori products, form on free amino groups (1). Further complex molecular rearrangements produce irreversible advanced glycation end products (AGEs):1 heterogeneous structures of yellow-brown color, characteristic fluorescence, and a propensity to form cross-links, which generate reactive oxygen intermediates and interact with specific cellular receptors (1-4). The presence of AGEs in tissue has been linked to development of vasculopathy, especially in the setting of diabetes (1, 3). AGE-modified adducts on long-lived proteins in extracellular matrix alter basement membrane structure by trapping plasma macromolecules and by increasing vessel wall rigidity through formation of cross-links (3). The principal means through which AGEs influence cellular properties is by binding to specific receptors (4-6), the best characterized of which is the receptor for AGEs (RAGE), a member of the immunoglobulin superfamily expressed by endothelial cells (ECs), smooth muscle cells, and mononuclear phagocytes (7), cells central to both vascular homeostasis and the pathogenesis of vascular lesions. A potential role for RAGE in vascular dysfunction is suggested by two lines of evidence: ( a ) engagement of AGEs by cellular RAGE affects critical properties of these cells in a manner contributory to vascular dysfunction (4); and ( b ) there is enhanced expression of RAGE in diabetic vasculopathy and in arteriosclerotic and other vascular lesions, such as inflammatory vasculitides (8).Increased vascular permeability is characteristic of diabetic vasculopathy (9), even at the earliest stages in which microalbuminuria may be the only harbinger of vascular complications yet to come (10). As ECs are the critical guardians of vascular barrier function, we postulated that AGEs in plasma or the subendothelium would promote vascular hyperpermeability by interacting with RAGE. We demonstrate that when diabetic rat red cells bearing AGEs are infused into normal animals, increased vascular permeability results, an effect which is prevented by blockade of RAGE. Hyperperme...

Calcitriol Treatment Increases Serum Levels of the Soluble Receptor of Advanced Glycation End Products in Hemodialysis Patients with Secondary Hyperparathyroidism

“…RAGE is involved in many pathological states, such as vascular disease, diabetic complications, and inflammatory diseases (Wautier et al 1996;Schmidt et al 2001;. In particular, sRAGE acts as a decoy receptor to inhibit the AGE-RAGE interaction and has protective 25D, 25 dihydroxyvitamin D 3 ; 1,25D, 1,25 dihydroxyvitamin D 3 ; PTH, parathyroid hormone; ALP, alkaline phosphatase; hsCRP, highly sensitivity C-reactive protein; sRAGE, soluble receptor for advanced glycation end products; EN-RAGE, extracellular newly identified RAGE-binding protein; IL-6, interleukin-6.…”

Advanced glycation end products and their receptors co-localise in rat organs susceptible to diabetic microvascular injury

“…Recent studies which blocked the action of RAGE using recombinant RAGE prevented the early increase in permeability that is observed in diabetic rats [53]. Further assessment of the functional and morphological sequelae to interference of this receptor-ligand interaction with modalities such as recombinant RAGE are warranted.…”

Advanced Glycation End Products-driven Angiogenesis in Vitro

“…Dolhofer-Bliesener et al (43) have shown that, in human diabetic subjects, the serum level of AGE was associated with the state of late complications, particularly in cases with retinopathy. Wautier et al (44) reported that infusion of diabetic red blood cells into normal rats can induce vascular hyperpermeability, which was completely inhibited by anti-RAGE IgG; they also demonstrated that an antioxidant, probucol, can similarly reverse the red blood cell transfer-induced vascular permeability, suggesting a role of AGE-RAGE interactions and the involvement of an oxidant stress-sensitive pathway in the development of hyperpermeability. Recent clinical studies at different institutions have established that intraocular concentrations of VEGF correlated with active neovascularization (45,46).…”