End-stage glomerulosclerosis constitutes a major complication of diabetes mellitus. The fact that the glomerular lesions of both type I and type II diabetes are similar suggests that abnormalities in glucose metabolism may participate in their development. Hyper-glycemia leads to the accumulation of advanced glycosylation end-products which participate in abnormal, non- metabolizable cross-linking of extra-cellular matrix components. Their accumulation may contribute to the sclerosis observed in diabetics, since AGEs trigger a large number of biological reactions through surface receptors that have been characterized on macrophages, endothelial cells, and human and rat mesangial cells. Mesangial cells plated on various components of glycosylated extracellular matrix produce an excess of fibronectin. Using normal mouse mesangial cells, we investigated the effect of AGE on the synthesis of the basement membrane components. Cells plated on AGE showed increased mRNA levels of collagen type IV, proteoglycan heparan sulfate, and laminin A and B chains using the RNase protection assay. There was also an increased release of collagen type IV in the medium. The rate of transcription, measured by nuclear run-off assays, was also stimulated in cells plated on glycosylated bovine serum albumin. These observations provide further evidence that the accumulation of extra-cellular matrix components in diabetics is regulated at the gene level.
