Advanced glycation end products and their receptors co-localise in rat organs susceptible to diabetic microvascular injury (original) (raw)
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Effect of diabetes and aminoguanidine therapy on renal advanced glycation end-product binding
Kidney International, 1999
Effect of diabetes and aminoguanidine therapy on renal adbeen shown to inhibit advanced glycation end-product vanced glycation end-product binding. (AGE) formation and cross-linking in the streptozocin Background. Advanced glycation end-products (AGEs) diabetic rat [2]. Aminoguanidine does not interfere with have been implicated in the pathogenesis of diabetic nephropathe formation of Amadori products such as glycated hethy, and aminoguanidine (AG) has been shown to decrease moglobin (Hb), but acts to inhibit subsequent rearrangethe accumulation of AGEs in the diabetic kidney. ments that are essential for cross-linking reactions [3]. Methods. This study investigates changes in AGE binding associated with diabetes in the rat kidney using in vitro and in Hemoglobin in the presence of glucose has been shown vivo autoradiographic techniques. Male Sprague-Dawley rats in vivo to form advanced glycated Hb [4]. Furthermore, were randomized into control and diabetic groups with and AG has been shown to decrease AGE-Hb, consistent without AG treatment and were sacrificed after three weeks. with the action of AG being distal to the formation Frozen kidney sections (20 m) were incubated with [ 125 I]-AGEof glycated Hb (HbA1c) [4]. Advanced glycation end-RNase or [ 125 I]-AGE-BSA. To localize the AGE binding site, products have been implicated in a number of biological in vivo autoradiography was performed by injection of 15 Ci of [ 125 I]-AGE-BSA into the abdominal aorta of the rat. processes, particularly in the pathogenesis of diabetic Results. Low-affinity binding sites specific for AGEs in the complications and aging [5].
Diabetes, 1999
Advanced glycation end products (AGEs) are nonenzymatic glycosylated adducts of proteins that accumulate in vascular tissue during diabetes and aging. The aim of this work was to study the role of AGEs and of the oxidative mechanisms in diabetes-induced changes in vascular permeability. Intravital videomicroscopy was used to study albumin microvascular leakage in cremaster muscle. The extravasation of a fluorescent macromolecular tracer (fluorescein isothiocyanatealbumin) was measured for 1 h and, after computeraided image analysis, was expressed as variations of normalized gray levels (arbitrary units). Extravasation of the macromolecular tracer was much higher in diabetic rats than in control rats (slope of extravasation versus time increased by >100%, P < 10 -4 ). This increase was significantly inhibited when we blocked AGEs binding to their endothelial receptor by intravenous bolus of soluble recombinant receptor to AGEs (rR-RAGE) (slope of extravasation versus time decreased by 19, 30, and 40%, for 0.5, 2.5, and 5.15 mg/kg rR-RAGE, respectively) or by a 6 mg/kg intravenous bolus of antibody against RAGE (slope decreased by 53%). Systemic injection of probucol (an antioxidant) also significantly inhibited the increase in the extravasation of the macromolecular tracer occurring in experimental diabetes (slope decreased by 51%, P < 10 -4 ). These results strongly suggest that in experimental diabetes the interaction of circulating AGEs and endothelial RAGE mediates albumin micro-vascular leakage, possibly via AGE-RAGE-dependent e n h a n c e d oxidant stress. D i a b e t e s 48:2052-2058,
Advanced glycation end products and the kidney
AJP: Renal Physiology, 2005
Advanced glycation end products (AGEs) are a heterogeneous group of protein and lipids to which sugar residues are covalently bound. AGE formation is increased in situations with hyperglycemia (e.g., diabetes mellitus) and is also stimulated by oxidative stress, for example in uremia. It appears that activation of the renin-angiotensin system may contribute to AGE formation through various mechanisms. Although AGEs could nonspecifically bind to basement membranes and modify their properties, they also induce specific cellular responses including the release of profibrogenic and proinflammatory cytokines by interacting with the receptor for AGE (RAGE). However, additional receptors could bind AGEs, adding to the complexity of this system. The kidney is both: culprit and target of AGEs. A decrease in renal function increases circulating AGE concentrations by reduced clearance as well as increased formation. On the other hand, AGEs are involved in the structural changes of progressive ...
Diabetes, advanced glycation endproducts and vascular disease
Vascular Medicine, 1998
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.
Advanced glycation end products, their receptors and diabetic angiopathy
Journal of the Peripheral Nervous System, 2002
The role of chronic hyperglycemia in the development of diabetic microvascular complications and in neuropathy has been clearly established by intervention studies. However, the biochemical or cellular links between elevated blood glucose levels, and the vascular lesions remain incompletely understood. This review focuses on the consequences of hyperglycemia on the formation of advanced glycation end-products (AGEs), and on the role of AGEs and of their specific receptors (RAGE) in the functional and anatomical alterations of the vascular wall. AGEs are formed during the Maillard reaction by the binding of aldoses on free NH 2 groups of proteins, which, after a cascade of molecular rearrangements, result in molecules of brown color and specific fluorescence. Experimental studies have indicated that the binding of AGEs to RAGE activates cells, particularly monocytes and endothelial cells. Activated endothelial cells produce cytokines, and express adhesion molecules and tissue factor. The role of AGEs in increased oxidative stress, and in the functional alterations in vascular tone control observed in diabetes, in part related to a reduction in nitric oxide, is also discussed. The microvascular retinal, glomerular and nerve lesions induced by experimental diabetes in animals are prevented by an inhibitor of AGEs formation, aminoguanidine. The administration in diabetic animals of recombinant RAGE, which hinders AGEs-RAGE interaction, prevents hyperpermeability and vascular lesions. These data suggest a central role of AGEs and RAGE in the development of chronic complications of diabetes.
Advanced glycation end products and the progressive course of renal disease
American Journal of Kidney Diseases, 2001
In experimental and human diabetic nephropathy (DN), it has been shown that advanced glycation end products (AGEs), in particular, carboxymethyl-lysine and pentosidine, accumulate with malondialdehyde in glomerular lesions in relation to disease severity and in the presence of an upregulated receptor for AGE (RAGE) in podocytes. Toxic effects of AGEs result from structural and functional alterations in plasma and extracellular matrix (ECM) proteins, in particular, from cross-linking of proteins and interaction of AGEs with their receptors and/or binding proteins. In mesangial and endothelial cells, the AGE-RAGE interaction caused enhanced formation of oxygen radicals with subsequent activation of nuclear factor-B and release of pro-inflammatory cytokines (interleukin-6, tumor necrosis factor-␣), growth factors (transforming growth factor-1 [TGF-1], insulin-like growth factor-1), and adhesion molecules (vascular cell adhesion molecule-1, intercellular adhesion molecule-1). In tubular cells, incubation with AGE albumin was followed by stimulation of the mitogen-activating protein (MAP) kinase pathway and its downstream target, the activating protien-1 (AP-1) complex, TGF-1 overexpression, enhanced protein kinase C activity, decreased cell proliferation, and impaired protein degradation rate, in part caused by decreased cathepsin activities. The pathogenic relevance of AGEs was further verified by in vivo experiments in euglycemic rats and mice by the parenteral administration of AGE albumin, leading in the glomeruli to TGF-1 overproduction, enhanced gene expression of ECM proteins, and morphological lesions similar to those of DN. Evidence for the pathogenic relevance of AGEs in DN also comes from experimental studies in which the formation and/or action of AGEs was modulated by aminoguanidine, OPB-9195, pyridoxamine, soluble RAGEs, serine protease trypsin, and antioxidants, resulting in improved cell and/or renal function.
Advanced glycation end products (AGEs)- mediated diabetic vascular complications
2017
Diwesh Chawla*1; Ashok Kumar Tripathi2 ; Meera Sikka3 1Central Research Laboratory, Multi-disciplinary Research Unit, University College of Medical Sciences (University of Delhi) and G.T.B. Hospital, Dilshad Garden, Delhi-110095, India. 2Biochemistry and Immunology Laboratory, Department of Biochemistry, University College of Medical Sciences (University of Delhi) and G.T.B. Hospital, Dilshad Garden, Delhi-110095, India. 3Department of Pathology, University College of Medical Sciences (University of Delhi) and G.T.B. Hospital, Dilshad Garden, Delhi-110095, India. Correspondence to: Diwesh Chawla, Central Research Laboratory, Multi-disciplinary Research Unit, University College of Medical Sciences (University of Delhi) and G.T.B. Hospital, Dilshad Garden, Delhi 110095, India. Email: diweshchawla@yahoo.co.in Chapter 1 Advances in Biochemistry & Applications in Medicine
Clinical hemorheology and microcirculation, 2010
Elevated glucose concentration increases oxidation and Advanced Glycation End product (AGE) formation. The binding of circulatory AGEs or AGEs included in erythrocyte membrane to the receptor for AGEs (RAGE) generates in endothelial cells an oxidative stress and enhances the expression of inflammatory molecules. Engagement of RAGE by AGEs and subsequent signaling plays an important role in the development of diabetic complications. Soluble RAGE isoforms (sRAGE) neutralize the ligand-mediated damage by acting as a decoy. If the expression of RAGE is upregulated during the pathogenesis of inflammatory diseases, sRAGE mostly found decreased when complications ensue. By modulating RAGE isoform expression, it could be possible to reduce the incidence of complications. This review focused on the capability of Angiotensin Receptor Blockers (ARBs), which are used to treat patients with hypertension and/or diabetes, to modulate RAGE isoform expression because some data reported the interfere...
Diabetologia, 1996
The presence of excessive amounts of advanced glycation end products (AGE) in tissues or in the circulation may critically affect the progression of diabetic nephropathy. Circulating AGE levels, mainly in the form of small peptides, increase in diabetic patients or in patients with end-stage renal disease. This rise correlates with the severity of the nephropathy. However, so far little is known about the fate of AGE-proteins and AGE-peptides in renal tissue, and in order to elucidate this issue we undertook the present study. AGE-bovine serum albumin (AGE-BSA) and AGE-peptides were prepared, characterized by spectrophotometry, spectrofluoromerry, chromatography and SDS-PAGE. AGE-peptides reacted in vitro with LDL producing biochemical and ultrastructural modifications. Using colloidal gold post-embedding immunoelectron microscopy with an anti-AGE antibody generated in our laboratory, we followed, in a short-term kinetic study, the cellular and sub-cellular localisation of circulating AGE-products throughout the nephron. AGE-peptides or AGE-BSA were injected into otherwise normal rats and detected by protein A-gold immunocytochemistry after 15, 30 or 45 min of circulation.