3-deoxyglucosone and AGEs in uremic complications: Inactivation of glutathione peroxidase by 3-deoxyglucosone

Abstract

3-Deoxyglucosone (3-DG) is accumulated not only in uremic serum but also in uremic erythrocytes. 3-DG rapidly reacts with protein amino groups to form advanced glycation end products (AGEs) such as imidazolone, pyrraline, and N∈-(carboxymethyl)lysine, among which imidazolone is the AGE that is most specific for 3-DG. In diabetes, hyperglycemia enhances the synthesis of 3-DG via the Maillard reaction and the polyol pathway and thereby leads to its high plasma and erythrocyte levels. In uremia, however, the decreased catabolism of 3-DG that may be due to the loss of 3-DG reductase activity in the end-stage kidneys may lead to a high plasma 3-DG level. The elevated 3-DG levels in uremic patients may promote the formation of AGEs such as imidazolone in erythrocytes, aortas, and dialysis-related amyloid deposits. Treatment with an aldose reductase inhibitor reduced the erythrocyte levels of 3-DG and AGEs such as imidazolone in diabetic uremic patients. This finding demonstrates an important role of the polyol pathway in the formation of erythrocyte 3-DG and AGEs. The erythrocyte levels of 3-DG are elevated in not only diabetic uremic but also nondiabetic uremic patients. 3-DG showed some cytotoxicities by inducing intracellular oxidative stress. In contrast, oxidative stress was demonstrated to cause accumulation of intracellular 3-DG. Recently, we have demonstrated that 3-DG inactivates intracellular enzymes such as glutathione peroxidase, a key enzyme in the detoxification of hydrogen peroxide. Thus, intracellular accumulation of 3-DG may enhance oxidative stress by inactivating the antioxidant enzymes. In conclusion, 3-DG may play a principal role in the development of uremic complications, such as dialysis-related amyloidosis, atherosclerosis, and enhanced oxidative stress.