Sugiyama S, Miyata T, Inagi R, Kurokawa K
Department of Nephrology, Chukyo Hospital, Nagoya, Japan.
Int J Mol Med. 1998 Nov;2(5):561-5. doi: 10.3892/ijmm.2.5.561.
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.
透析相关性淀粉样变性被认为是长期透析患者严重的骨和关节并发症。β2-微球蛋白已被证明是淀粉样纤维的主要成分。然而，这种疾病的分子发病机制仍然未知。最近的生化和免疫组织学研究在淀粉样纤维中发现了β2-微球蛋白的一种新修饰，即晚期糖基化终产物（AGEs）。AGEs由非酶糖基化和氧化（糖氧化）反应形成。在非糖尿病透析患者的血浆蛋白和皮肤胶原蛋白中，诸如戊糖苷和羧甲基赖氨酸（CML）等AGEs的水平比正常受试者高出几倍。尿毒症中AGE的积累不能归因于高血糖，也不能简单地归因于其肾脏清除率降低。最近，越来越多的证据表明，在尿毒症中，源自碳水化合物和脂质的羰基化合物增加会修饰蛋白质，不仅导致AGEs的产生增加，还会导致晚期脂质氧化终产物（ALEs）的产生增加。因此，尿毒症可能是一种羰基过载状态，会对蛋白质造成潜在损害（“羰基应激”）。使用针对AGEs和ALEs的特异性抗体进行的免疫组织化学研究，在长期存在的β2-微球蛋白淀粉样沉积物中发现了羰基应激。此外，经羰基应激修饰的蛋白质对几种类型的细胞表现出多种生物学活性，这可能部分解释了透析性关节病。
