We propose to investigate the role of glucose-derived protein cross-links in the pathogenesis of diabetic renal structural changes, using a newly described inhibitor of glucose-derived cross-linking, previously developed quantitative biochemical methods, and established morphologic techniques.
The specific aims of the studies described in this proposal are to: I) Quantitate advanced glycosylation product accumulation and glucose-derived collagen cross-linking in glomerular connective tissue matrix obtained from the most extensively characterized animal model of diabetic glomeulopathy (alloxanized Lewis rats), using biochemical methods previously developed for these specific analyses; II) Quantitate advanced glycosylation product accumulation and glucose-derived collagen cross-linking in skin punch biopsy specimens from groups of diabetic clinic patients having strictly defined degrees of microvascular and macrovascular disease; III) Determine the extent of diabetes-associated morphologic changes in identical samples of these same animal and human tissues, using established immunohistochemical and electron microscopic techniques; IV) Characterize the relationship between accumulated glucose- derived protein cross-links and the development of structural changes in these diabetic tissues; V) Evaluate the potential preventitive and reversibility effects of aminoguanidine, an inhibitor of glucose-derived protein cross- linking, on the quantity of accumulated advanced glycosylation products, the degree of glucose-derived cross-linking, and the extent of morphologic changes in glomerular specimens from diabetic animals.
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