Advanced glycoxidation endproducts interactions

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AGEs can cause pathological changes in tissues by multiple receptor-dependent and receptor-independent processes. A characteristic of AGEs is their ability for covalent crosslink formation that leads to alterations of the structure and function of proteins (5,6,41). It is now clear that short- and long-lived molecules alike including circulating proteins, lipids, or intracellular proteins and nucleic acids can be modified (5,6,41,48). Glycation of one such molecule, low-density lipoprotein (LDL), leads to its delayed receptor-mediated clearance and subsequent deposition in the vessel wall, contributing to atherosclerosis and macrovascular disease (5,6,41,48).

Intracellular AGEs are reported to form at a rate up to 14-fold faster under high-glucose conditions, although the impact of intracellular glycation can be partially countered by the high turnover and short half-life of many cellular proteins (49).

Experimental work conducted over the last 15 years has led to the recognition of an AGE-receptor system and soluble AGE-binding proteins. The interaction of AGEs with these proteins leads either to endocytosis and degradation or to cellular activation (5,6,41). In addition to these receptor pathways, AGEs can also induce cellular activation via intracellularly generated glycoxidant derivatives or via free radical generation (5,6,41).

The first cell surface AGE-binding protein receptor identified was AGE-R1, with characteristic membrane-spanning and signal domains homologous to a 48kD component of the oligosaccharyltransferase complex-48 (5,41,50-52).This component has recently been shown to be linked to AGE removal and supression of undue oxidative stress and cell-activation events (53). An 80kD protein or AGE-R2, identical to a tyrosine-phospho-rylated protein located largely within the plasma membrane was found involved in binding and forming complexes with adaptor molecules such as Shc and GRB-2. AGEs are highly efficient stimuli for AGE-R2 phosphorylation indicating its possible involvement in AGE-signaling (5,41,54-57). AGE-receptor-3 or Galectin-3, known as Mac-2 or carbohydrate-binding protein-35, is also known to interact with the P-galactoside residue of several cell surface and extracellular matrix (ECM) glycoproteins, via the carbohydrate recognition domain (5,41,54-58). AGE-R3 or Galectin-3 is only weakly detectable on cell surfaces under basal conditions, but becomes highly expressed with age and diabetes (55). AGE-R3 exhibits high-binding affinity for AGEs and appears to enhance AGE internalization and degradation in macrophages, astrocytes, and endothelial cells (5,41,54-57).

The expression of AGE receptors in mesangial cells and monocytes/macrophages in NOD mice and in diabetic patients was found to correlate with the severity of diabetic complications (5,41,52). AGE-receptor-3 knockout mice exhibited accelerated diabetic glomerulopathy, associated with marked renal/glomerular AGE accumulation implying a beneficial role for AGE-R3 in AGE clearance (58). Recent in vitro studies imply a possible direct role of Galectin-3 in the pathogenesis of atherosclerosis and diabetic glomerulopathy (5,41,57,58).

The receptor for advanced glycation end-products (RAGE), a well-characterized multiligand member of the immunoglobulin superfamily, is viewed as an AGE-binding intracellular signal-transducing peptide, which mediates diverse cellular responses rather than as a receptor involved in AGE endocytosis and turnover. Several other distinct ligands have been described for RAGE including amyloid, amphoterin, and S100/ calgranulins (5,41,59-62). RAGE is present at low levels in adult animals and humans, but is later upregulated regardless of diabetic vascular disease (62). RAGE expression is increased in sites of increased AGE accumulation such as vasculature, neurons, lymphocytes, and tissue-invading mononuclear phagocytes. In the kidney, RAGE is expressed in glomerular visceral epithelial cells (podocytes) but not in mesangium or glomerular endothelium (59). Diabetic RAGE-transgenic mice exhibit renal vascular changes characteristic of diabetic nephropathy (60). In contrast, brief infusion of a soluble truncated RAGE is reported to intercept diverse processes such as endothelial leakage, atherosclerosis, and inflammatory bowel disease (59).

Other well-studied AGE-binding molecules are the macrophage scavenger receptors, class A (MSR-A) and class B (MSR-B). MSR-A, better known as receptors for oxidized LDL may also play a role in endocytic uptake and degradation of AGE-proteins in vivo (5,41,63,64). CD36, a member of MSR-B receptors, is a highly glycosylated 88-kD protein expressed on macrophages which, although not restricted to AGE uptake, may contribute to AGE-mediated foam cell formation (65). The class B type I scavenger receptor (SR-BI) is also considered as an AGE-interactive molecule; it is suggested that it contributes to reverse cholesterol transport by suppressing selective uptake of high-density lipoprotein cholesterol efflux (HDL-CE) by liver and cholesterol efflux from peripheral cells to HDL (66). Additionally, recently cloned LOX-1 and SREC, novel scavenger receptors expressed in vascular endothelial cells are awaiting studies to determine their affinity for AGE-proteins (67).

Another molecule with significant AGE-binding affinity and intriguing anti-AGE properties is lysozyme. Lysozyme is a well-characterized natural host-defense protein thought to exert antibacterial effects through the catalytic degradation of the peptidogly-can component of the bacterial wall (68). Lysozyme is found in saliva, nasal secretions, milk, mucus, serum, and in lysosomes of neutrophils and macrophages. Against all predictions, however, a novel AGE-binding site was mapped to a 17-18 amino acid hydrophilic domain (ABCD motif or AGE-binding cysteine-bounded domain), bounded on both sides by cysteines and located within one of the two lysozyme catalytic regions (68). Lysozyme enhances the uptake and degradation of AGE proteins by macrophages, apparently via an AGE-specific receptor pathway not well defined thus far (68). Lysozyme administration to diabetic mice, however, increases AGE clearance, suppresses macrophage and mesangial cell-specific gene activation in vitro, and improves albuminuria, thus presenting an unusual combination of advantages, which have stimulated interest in this native substance as a potential therapeutic target (69). A novel receptor that mediates AGE-induced chemotaxis in rabbit smooth muscle cells has also been identified (70).

The genomic organization, chromosomal location, and several prevalent gene polymorphisms of some of the AGE-R-related molecules have come to light in the past few years. For instance, a recent screening using single-strand conformational polymorphism analysis and direct sequencing of allelic polymerase chain reaction fragments in 48 type 1 diabetics with or without nephropathy showed variants of AGE receptors, mutations, and polymorphisms that correlated with the presence and the severity of complications, albeit only weakly (71).

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Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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