Modification of beta 2m with advanced glycation end products as observed in dialysis-related amyloidosis by 3-DG accumulating in uremic serum.
beta 2microglobulin (beta 2m) isolated from the amyloid deposits in patients with dialysis-related amyloidosis (DRA) has been demonstrated to be modified with advanced glycation end products (AGEs). We demonstrated that AGE was localized to amyloid deposits in patients with DRA by immunohistochemistry using a monoclonal anti-AGE antibody. To clarify the mechanism of AGE modification of beta 2m-amyloid, we studied the effects of 3-deoxyglucosone (3-DG), a potent protein crosslinking the intermediate of the Maillard reaction, on the AGE modification of beta 2m, and quantified the serum levels of 3-DG in patients undergoing hemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD), and undialyzed patients. The serum levels of 3-DG were markedly increased in the dialyzed and undialyzed uremic patients. Although the serum level of 3-DG decreased after HD with a mean reduction rate of 67%, it was still significantly higher than in normal serum. Incubation of beta 2m with 3-DG at 37 degrees C emitted fluorescence characteristic for AGE, and caused AGE modification and dimer formation of beta 2m as demonstrated by Western blotting using the same monoclonal anti-AGE antibody used for immunohistochemical demonstration of AGE in DRA. The AGE-modified dimer of beta 2m could be extracted from the amyloid tissue of a patient with DRA. 3-DG showed more intense and faster reactivity with beta 2m to form AGE and dimer as compared with glucose, and aminoguanidine suppressed the AGE and dimer formation of beta 2m by 3-DG. In conclusion, 3-DG accumulating in uremic serum may be involved in the AGE modification of beta 2m-amyloid.
Niwa
T
T
Nagoya University Branch Hospital, Japan.
Katsuzaki
T
T
Momoi
T
T
Miyazaki
T
T
Ogawa
H
H
Saito
A
A
Miyazaki
S
S
Maeda
K
K
Tatemichi
N
N
Takei
Y
Y
D000686:Amyloidosis / Q000209:etiology / Q000378:metabolism*; D000911:Antibodies, Monoclonal; D015153:Blotting, Western; D003847:Deoxyglucose / Q000031:analogs & derivatives* / Q000097:blood; D005260:Female; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D010531:Peritoneal Dialysis, Continuous Ambulatory / Q000009:adverse effects*; D006435:Renal Dialysis / Q000009:adverse effects*; D014511:Uremia / Q000150:complications / Q000378:metabolism / Q000628:therapy*; D001613:beta 2-Microglobulin / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D017127:Glycation End Products, Advanced; D001613:beta 2-Microglobulin; D003847:Deoxyglucose; C016350:3-deoxyglucosone