Glucose Auto Oxidation and Formation of AGE

AGE, predominantly NG-(carboxymethyl) lysine (CML), pentosidine, and pyrraline, can arise in excess in diabetes from sequential glycation and oxidation reactions termed glycooxidation or auto-oxidative glycosylation (30,34,47,48,88,89). Formation of CML and pentosidine in particular depend on oxidative processes (31).

Glucose and other reducing sugars can be auto-oxidized by metal-catalyzed oxida-tive processes that generate ROS and the reactive intermediate dicarbonyl, glyoxal (Fig. 2). The latter reacts with amino groups on protein to form CML (90).

Pyrraline Age
Fig. 2. Metabolic pathways in the formation of AGE. (For description, see text.) RAGE, receptor for AGE; MAPK, mitogen-activated protein kinase; AP1, activator protein 1; NF-kB, nuclear factor-KB. (For other abbreviations, see Fig. 1.)

Pentosidine is also formed from the Amadori product (glucose-derived 1-amino-1-deoxyfructose lysine adducts) by oxidative reactions (31,91). The Amadori product may decompose to 3-deoxyglucosone, which reacts with amino groups of proteins to form pyrraline (47). The reactive diacarbonyl intermediate methylglyoxal, which also participates in formation of AGE adducts, is generated from glyceraldehydes 3-phosphate and DHAP (34). In renal biopsies obtained from humans with DN (31), the glycooxidation products CML and pentosidine were colocalized by immuno-histochemical staining with the lipid peroxidation product MDA (a marker of oxidative stress). These products were colocalized in the expanded glomerular mesangium and in thickened glomerular capillaries in early DN and in nodular glomerular accumulation of matrix and renal arteriolar walls in advanced DN (31). By contrast, pyrraline did not colocalize with MDA in these areas. The findings suggest that accumulation, and presumably increased formation of at least some AGE reflects local oxidative stress (31).

Formation of reactive AGE precursors may result in renal and other cell injury by a variety of mechanisms (Fig. 2) involving direct alterations of protein function and/or structure (34,91,92). In DN, these include alterations in matrix proteins such as intermolecular crosslinking of collagen (34,83,91,92). However, in addition to these effects, extracellular AGE-modified proteins also interact with several cell surface receptors (33,34,93,94), including the receptor for AGE (RAGE), a multiligand member of the immunoglobulin superfamily of cell surface molecules (33). Activation of RAGE increases ROS generation in EC and MC (32,83,95). This increase (Fig. 2), which may be mediated via RAGE stimulation of NADPH oxidase, is part of a cell signaling cascade by which extracellular AGE activates PKC, mitogen-activated protein kinase, TGF-P and the pleiotropic gene transcription factors, nuclear factor (NF)-kB, activator protein 1, and p21 (32-34,87).

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