Implication of the glycoxidation and lipoxidation reactions in the pathogenesis of dialysis-related amyloidosis (Review).
Dialysis-related amyloidosis is recognized as a serious bone and joint complication in long-term dialysis patients. Beta2-microglobulin has been demonstrated to be a major constituent of the amyloid fibrils. However, the molecular pathogenesis of this disorder remains unknown. Recent biochemical and immunohistological studies have identified a new modification of beta2-microglobulin in the amyloid fibrils, i.e., the advanced glycation end products (AGEs). AGEs are formed by non-enzymatic glycative and oxidative (glycoxidation) reactions. The levels of AGEs, such as pentosidine and carboxymethyllysine (CML), are elevated in both the plasma proteins and skin collagen of non-diabetic dialysis patients several times more than in normal subjects. The AGE accumulation in uremia cannot be attributed to hyperglycemia, nor simply to their decreased renal clearance. Recently, gathered evidence has suggested that, in uremia, an increase in carbonyl compounds, derived from both carbohydrates and lipids, modifies proteins, leading to the augmentation of the production of not only AGEs, but also the advanced lipoxidation end products (ALEs). Uremia might thus be a state of carbonyl overload with potentially damaging proteins ('carbonyl stress'). Immunohistochemical studies, with antibodies specific to AGEs and ALEs, identified carbonyl stress in long-lived beta2-microglobulin amyloid deposits. Furthermore, proteins modified by carbonyl stress exhibit a variety of biological activities towards several types of cells, which might partially account for dialysis arthropathies.
Sugiyama
S
S
Department of Nephrology, Chukyo Hospital, Nagoya, Japan.
Miyata
T
T
Inagi
R
R
Kurokawa
K
K
D000682:Amyloid / Q000378:metabolism; D000686:Amyloidosis / Q000209:etiology* / Q000378:metabolism* / Q000503:physiopathology; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D050050:Protein Carbonylation; D006435:Renal Dialysis / Q000009:adverse effects*; D014511:Uremia / Q000378:metabolism; D001613:beta 2-Microglobulin / Q000378:metabolism
D000682:Amyloid; D017127:Glycation End Products, Advanced; D001613:beta 2-Microglobulin