Increased Adhesion of Erythrocytes to Endothelial Cells in Diabetes Mellitus and Its Relation to Vascular Complications

Wautier, Jean‐Luc; Paton, R C; Wautier, Marie‐Paule; Pintigny, D; Abadie, Eric; Passa, P; Caen, Jacques P.

doi:10.1056/nejm198107303050501

Cited by 198 publications

(99 citation statements)

References 16 publications

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“…AGE-modified structures, whether present on plasma proteins or diabetic red cells, display increased adhesivity for endothelium because of their binding to cell surface RAGE (4,(17)(18)(19) H-inulin in Fig. 1, A and B , respectively) across cell monolayers compared with normal red cells, which were comparable with untreated controls.…”

Section: Resultsmentioning

confidence: 72%

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

Wautier¹,

Zoukourian²,

Chappey³

et al. 1996

J. Clin. Invest.

522

325

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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...

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Section: Resultsmentioning

confidence: 72%

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

Wautier¹,

Zoukourian²,

Chappey³

et al. 1996

J. Clin. Invest.

522

325

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show abstract

“…In some previous studies, an increased PF concentration was found in diabetic patients with microalbuminuria [12,13], but this was not confirmed by other investigators [3,4]. The aim of this study was to clarify this controversial issue, and to evaluate the PF concentration as a possible marker for early diabetic nephropathy.…”

mentioning

confidence: 73%

“…Plasma fibronectin (PF) plays a role in erythrocyte or platelet adhesion to vascular endothelium or subendothelial collagen [3,4].…”

mentioning

confidence: 99%

Can We Use Plasma Fibronectin Levels as a Marker for Early Diabetic Nephropathy.

et al. 1995

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Abstract. Although increased plasma fibronectin (PF) levels have been found in diabetic patients with microalbuminuria, there is still controversy about its clinical implication for detecting early diabetic nephropathy.To evaluate the PF concentration as a possible marker for early diabetic nephropathy, three groups of sex-and age-matched patients were studied I) 22 insulin dependent diabetic (IDDM) patients with microalbuminuria (mean age ± SEM: 23.3 ± 3.6 years, mean urinary albumin excretion rate (AER) ± SEM: 47.1 ± 39.5 µg/min); II) 17 IDDM patients with normoalbuminuria (mean age: 23.4 ± 4.4 years, mean AER: 7.8 ± 2.1 µg/min) and III) 20 healthy control subjects (mean age: 22.6 ± 4.1 years, mean AER: 6.7 ± 2.1 µg/min). PF and urinary excretion of albumin were measured by an immunoturbidimetric method using commercially available kits (Boehringer Mannheim GMBH FRG, and Miles Lab., UK). The mean PF was significantly higher in the group with microalbuminuria (406.5 ± 122.9 µg/ml) than in the group with normoalbuminuria (295.6 ± 96.9 pg/ml, P<0.01) or in the control group (299.54 ± 105.5 µg/ml, P<0.01). A weak positive correlation was found between PF and urinary albumin values (r=0.35, P<0.05). There were no significant correlations between PF and the other variables such as age, duration of diabetes, body mass index, arterial blood pressure, fasting blood glucose, fructosamine and HbA1 in the diabetic patients or in the control group. Our results suggest that the PF concentration could be a weak marker for early diabetic nephropathy. We cannot therefore use PF instead of microalbuminuria because there is only a weak correlation between PF and microalbuminuria.

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“…[28][29][30][31] Anti-AGE antibodies or soluble RAGE inhibit the enhanced adhesion to endothelium when incubated with RBC from diabetic patients. 32 The accelerated clearance of diabetic rat RBC when infused in normal rats is prevented by the infusion of anti-RAGE antibody in the animal.…”

Section: -27mentioning

confidence: 99%

Diabetes, advanced glycation endproducts and vascular disease

Wautier¹,

Guillausseau

1998

Vasc Med

Self Cite

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Abstract:The high incidence of vascular complications in patients with diabetes mellitus remains incompletely understood. Several metabolic or endocrine abnormalities have been postulated as possible triggers for micro and macroangiopathies. This review article focuses on the consequences of hyperglycemia, leading to the formation of advanced glycation endproducts (AGE), on vascular function. Advanced glycation endproducts are the product of the binding of aldoses onto free amino groups of proteins or lipoproteins, which, after molecular rearrangement, result in a class of molecules of a brown color and specific fluorescence. Different cell membrane proteins have been shown to bind AGE and the best characterized receptor for AGE has been named RAGE. The AGE receptor is present on different cell types including endothelial cells, smooth muscle cells, lymphocytes and monocytes.Experimental studies have revealed that the binding of AGE to RAGE produces an activation of monocytes and endothelial cells. Activated endothelial cells produce interleukin and express vascular cell adhesion molecule and tissue factor. Advanced glycation endproducts, when infused into animals, induce an increase in vascular permeability. The blockade of RAGE by specific antibodies corrects the hypermeability observed in diabetic animals.The prevention of AGE formation by aminoguanidine treatment improves the microvascular lesions found in diabetic animals either in the retina or the glomerus. The infusion of recombinant RAGE in diabetic animals corrects hyperpermeability. The colocalization of RAGE and AGE at the microvascular site of the injury suggests that their interaction may play a significant role in the pathogenesis of diabetic vascular lesions.

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Increased Adhesion of Erythrocytes to Endothelial Cells in Diabetes Mellitus and Its Relation to Vascular Complications

Cited by 198 publications

References 16 publications

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

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

Can We Use Plasma Fibronectin Levels as a Marker for Early Diabetic Nephropathy.

Diabetes, advanced glycation endproducts and vascular disease

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