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

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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.