Role of advanced glycation end-product in the development and progression of diabetic nephropathy.

在糖尿病状态下，蛋白质发生糖基化反应（美拉德反应），晚期糖基化终产物（AGE）在各组织中积累。AGEs与巨噬细胞上的受体结合，并诱导细胞因子和一氧化氮（NO）的产生。经AGE修饰的细胞外基质具有抗蛋白水解降解的能力。为了探讨AGEs在糖尿病肾病进展中的作用，我们对糖尿病肾病患者、链脲佐菌素诱导的糖尿病大鼠肾脏和OLETF大鼠的肾活检标本进行了AGE和细胞外基质成分的免疫组化研究。在肾系膜区和肾小管中，AGEs在糖尿病肾脏中积累。特别是糖尿病肾的结节性病变，AGE被注意到。超高分辨扫描电镜显示结节性病变系膜基质网状增大。这些结果表明AGEs随糖尿病肾病的进展而积累。AGEs可能与系膜细胞上的受体结合，从而刺激其产生并抑制其蛋白水解降解。AGEs可能在糖尿病肾病的细胞外基质结构改变和肾小球硬化中起关键作用。

In diabetic state, glycation reaction of the proteins (Maillard reaction) undergoes and advanced glycation endproduct (AGE) accumulates in varous tissues. AGEs bind to the their receptors on the macrophages, and are known to induce the production of cytokines and nitric oxide (NO). Extracellular matrix with AGE modification is resistant to the proteolytic degradation. To explore the role of AGEs in the progression of the diabetic nephropathy, immunohistochemical studies of AGE and extracellular matrix components were performed in the kidney biopsy specimens of diabetic nephropathy patients, streptozotocin-induced diabetic rat kidney, and OLETF rat. In the mesangial area and tubules, AGEs were accumulated in the diabetic kidney. Especially in the nodular lesions of the diabetic kidneys, AGE were noted. By ultra-high resolution scanning electron microscopy showed enlarged meshwork of mesangial matrix of nodular lesions. These results indicated that AGEs accumulated with the progression of the diabetic nephropathy. AGEs may bind to the receptor on the mesangial cells and thus stimulate the production and inhibit the proteolytic degradations. AGEs may play a pivotal role in the alterations of the structual architecture of the extracellular matrix and glomerulosclerosis of the diabetic nephropathy.