3-deoxyglucosone and AGEs in uremic complications: inactivation of glutathione peroxidase by 3-deoxyglucosone.
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(epsilon)-(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.
Niwa
T
T
Nagoya University Daiko Medical Center, Nagoya, Japan. tniwa@med.nagoya-u.ac.jp
Tsukushi
S
S
D000686:Amyloidosis / Q000209:etiology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001161:Arteriosclerosis / Q000209:etiology; D002455:Cell Division / Q000187:drug effects; D003847:Deoxyglucose / Q000031:analogs & derivatives / Q000633:toxicity*; D004815:Epidermal Growth Factor / Q000096:biosynthesis; D004912:Erythrocytes / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000037:antagonists & inhibitors* / Q000097:blood; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors; D017127:Glycation End Products, Advanced / Q000097:blood*; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D018384:Oxidative Stress; D014511:Uremia / Q000097:blood* / Q000150:complications*
D017127:Glycation End Products, Advanced; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D004815:Epidermal Growth Factor; D003847:Deoxyglucose; D005979:Glutathione Peroxidase; D005980:Glutathione Reductase; C016350:3-deoxyglucosone; D005947:Glucose