Ultrastructure of nonenzymatically glycated mesangial matrix in diabetic nephropathy

Advanced protein glycation has been proposed as a major factor in the development of diabetic nephropathy. Advanced glycation end products (AGEs) have altered the structure of extracellular matrix component and impaired self association in vitro. To elucidate the role of AGEs in the progression of diabetic nephropathy, the present study was undertaken to localize glomerular AGEs immunohistochemically. Ultrastructural changes of the mesangial matrix were analyzed with high resolution scanning electron microscopy. No glomerular AGEs staining was noted in normal control kidney specimens, or in tissue from glomerulonephritis patients without diabetes mellitus. The mesangium showed a positive AGEs staining in advanced stages of diabetic nephropathy, and the most characteristic finding was the strong AGEs staining in nodular lesions. By high resolution scanning electron microscopy, control and diabetic mesangial matrices revealed a meshwork structure composed of fine fibrils (10 nm in width) and numerous pores (12 to 13 nm in diameter). In the nodular lesions, however, loosening of the meshwork was significant, and the diameter of the pores was enlarged (approximately 24 nm). This study provides the first immunohistochemical evidence that AGEs are localized in diabetic glomeruli, most notably to nodular lesions. Advanced glycation might play a role in the progression of diabetic nephropathy through impairment of the assembly of matrix proteins in vivo.