Glycation inactivation of the complement regulatory protein CD59 - A possible role in the pathogenesis of the vascular complications of human diabetes
Glycation inactivation of the complement regulatory protein CD59 - A possible role in the pathogenesis of the vascular complications of human diabetes
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DOI：
10.2337/diabetes.53.10.2653
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发表时间：
2004-10-01
期刊：
影响因子：
7.7
通讯作者：
Halperin, JA
中科院分区：
文献类型：
--
作者：
Qin, XB;Goldfine, A;Halperin, JA
微血管和大血管疾病是糖尿病人群发病率和死亡率的主要原因，但将高血糖症与这些并发症联系起来的细胞和分子机制仍不完全清楚。我们提出，在人类糖尿病中，补体调节蛋白CD59的糖化抑制增加了补体的膜攻击复合物（MAC）的沉积，从而导致更高的血管风险。我们在此报告1）抗糖化人CD59（hCD59）特异性抗体的产生和表征，2）用该抗体检测糖尿病受试者（而非非糖尿病受试者）肾脏和神经中与MAC共定位的糖化hCD59，以及3）糖尿病受试者红细胞中hCD59活性显著降低，这一发现与hCD59在体内的糖化失活一致。由于hCD 59作为MAC形成的特异性抑制剂，这些发现为据报道在糖尿病并发症的靶器官中发现的MAC沉积增加提供了分子解释。我们得出结论，糖化失活的hCD59，导致MAC沉积增加可能有助于广泛的血管病变，使人类糖尿病。
Micro- and macrovascular diseases are major causes of morbidity and mortality in the diabetic population, but the cellular and molecular mechanisms that link hyperglycemia to these complications remain incompletely understood. We proposed that in human diabetes, inhibition by glycation of the complement regulatory protein CD59 increases deposition of the membrane attack complex (MAC) of complement, contributing to the higher vascular risk. We report here 1) the generation and characterization of an anti-glycated human CD59 (hCD59) specific antibody, 2) the detection with this antibody of glycated hCD59 colocalized with MAC in kidneys and nerves from diabetic but not from nondiabetic subjects, and 3) a significantly reduced activity of hCD59 in erythrocytes from diabetic subjects, a finding consistent with glycation inactivation of hCD59 in vivo. Because hCD59 acts as a specific inhibitor of MAC formation, these findings provide a molecular explanation for the increased MAC deposition reportedly found in the target organs of diabetic complications. We conclude that glycation inactivation of hCD59 that leads to increased MAC deposition may contribute to the extensive vascular pathology that complicates human diabetes.