Implication of Altered Redox Regulation by Antioxidant Enzymes in the Increased Plasma Pentosidine, an Advanced Glycation End Product, in Uremia

Abstract

Pentosidine is an advanced glycation end product (AGE) formed during Maillard or browning reaction by non-enzymatic glycation and oxidation (glycoxidation). Recent studies demonstrated the increased plasma pentosidine levels not only in diabetic patients with hyperglycemia but also in normoglycemic uremic patients. The mechanism of increased glycoxidation reaction in uremia, however, remains unknown. As superoxide dismutases (SODs) and glutathione peroxidase (GPx) are antioxidant enzymes involved in the metabolism of H2O2which accelerates the glycoxidation reaction, we measured their activities by enzymatic assays in the plasma of normal and non-diabetic hemodialysis patients and examined a link between redox regulation by antioxidant enzymes and glycoxidation reaction. The activities of GPx were significantly lower in the plasma of hemodialysis patients than in normal subjects, whereas those of SODs were higher in the former than in the latter. As plasma SODs comprise three isozymes,i.e.,Cu/Zn-SOD, Mn-SOD, and extracellular (EC)-SOD, we determined the levels of each SOD isozyme by ELISAs. The plasma concentrations of Cu/Zn-SOD and EC-SOD were significantly higher in hemodialysis patients than in normal subjects, whereas those of Mn-SOD did not differ between the two groups. It is of note that GPx activities correlated inversely with pentosidine in the plasma of hemodialysis patients (r2= 0.262,P< 0.01). There was no significant correlation between total SOD activities and pentosidine levels in the plasma of hemodialysis patients, but, among the three SOD isozymes, the plasma EC-SOD levels correlated with the levels of pentosidine in hemodialysis patients (r2= 0.286,P< 0.05). As decreased GPx and increased SOD activities result in the increased H2O2generation, which accelerates the glycoxidation of protein, these data suggest a link of altered redox regulation by antioxidant enzymes to increased glycoxidation reaction in the uremic plasma. This paper provides the first time evidence for the possible involvement of enzymatic redox regulation in the non-enzymatic glycoxidation reactionin vivo.