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. These products participate in abnormal, non-metabolizable cross-linking of extra-cellular matrix components. Their accumulation may contribute to the sclerosis observed in diabetics. AGEs trigger a large number of biological reactions which are mediated by surface receptors that have been characterized on macrophages, endothelial cells, and human and rat mesangial cells. Mesangial cells plated on various glycosylated extracellular matrix components produce an increased amount 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 levels of the following mRNAs using the RNAse protection assay: collagen type IV, proteoglycan heparan sulfate, and laminin A and B chains. We also found an increased release of collagen type IV into the medium. The rate of transcription, measured by nuclear run-off assays, was also stimulated in cells plated on glycosylated bovine serum albumin. AGE receptor antibodies inhibited the observed increase in mRNAs. Antibodies to PDGF abrogated the AGE response. These observations provide further evidence that the accumulation of extracellular matrix components in diabetics is regulated at the gene level, and is correlated with an increase in mesangial cell turnover.
