Immunohistochemical detection of imidazolone, a novel advanced glycation end product, in kidneys and aortas of diabetic patients
Immunohistochemical detection of imidazolone, a novel advanced glycation end product, in kidneys and aortas of diabetic patients
复制标题
DOI：
10.1172/jci119285
复制
发表时间：
1997-03-15
影响因子：
15.9
通讯作者：
Takei, Y
中科院分区：
文献类型：
--
作者：
Niwa, T;Katsuzaki, T;Takei, Y
为了研究美拉德反应在糖尿病并发症发病机制中的作用，我们通过用 AGE 修饰的匙孔血蓝蛋白免疫小鼠，制备了数个抗晚期糖基化终末产物 (AGE) 的单克隆抗体克隆，并发现抗 AGE 抗体的一个克隆 (AG-1) 与新型 AGE 咪唑酮 A 和 B 发生特异性反应，从而产生了咪唑酮（咪唑啉酮，咪唑酮是胍基的反应产物）。精氨酸与 3-脱氧葡萄糖酮 (3-DG)（美拉德反应的反应中间体）的结合被发现是体外产生的 AGE 修饰蛋白的常见表位。我们使用单克隆抗咪唑酮抗体 ELISA 测定了糖尿病患者中咪唑酮的红细胞水平。发现糖尿病患者红细胞中的咪唑酮水平与健康受试者相比显着升高，然后我们使用该抗体通过免疫组织化学研究了从糖尿病患者获得的肾脏和主动脉中咪唑酮的定位。在糖尿病肾病晚期的结节性病变和扩张的肾小球系膜基质和肾动脉以及主动脉的动脉粥样硬化病变中检测到特异性咪唑酮免疫反应性。这项研究首先证明了咪唑酮在糖尿病肾病和动脉粥样硬化的特征性病变中的定位。这些结果与最近糖尿病患者血清 3-DG 水平升高的证明一起，强烈表明： 3-DG 产生的咪唑酮可能会导致肾病和动脉粥样硬化等长期糖尿病并发症的进展。
To investigate the role of the Maillard reaction in the pathogenesis of diabetic complications, we produced several clones of monoclonal antibodies against advanced glycation end products (AGEs) by immunizing mice with AGE-modified keyhole limpet hemocyanin, and found that one clone (AG-1) of the anti-AGE antibodies reacted specifically with imidazolones A and B, novel AGEs, Thus, the imidazolones, which are the reaction products of the guanidino group of arginine with 3-deoxyglucosone (3-DG), a reactive intermediate of the Maillard reaction, were found to be common epitopes of AGE-modified proteins produced in vitro, We determined the erythrocyte levels of imidazolone in diabetic patients using ELISA with the monoclonal anti-imidazolone antibody. The imidazolone levels in the erythrocytes of diabetic patients were found to be significantly increased as compared with those of healthy subjects, Then we studied the localization of imidazolone in the kidneys and aortas obtained from diabetic patients by immunohistochemistry using the antibody. Specific imidazolone immunoreactivity was detected in nodular lesions and expanded mesangial matrix of glomeruli, and renal arteries in an advanced stage of diabetic nephropathy, as well as in atherosclerotic lesions of aortas, This study first demonstrates the localization of imidazolone in the characteristic lesions of diabetic nephropathy and atherosclerosis, These results, taken together with a recent demonstration of increased serum 3-DG levels in diabetes, strongly suggest that imidazolone produced by 3-DG may contribute to the progression of long-term diabetic complications such as nephropathy and atherosclerosis.