Complement in the Vascular Complications of Diabetes

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DESCRIPTION (provided by applicant): The major goal of this proposal is to investigate glycated human CD59 as a surrogate bio-marker and predictor of vascular diabetic complications, with special focus on diabetic nephropathy and peripheral and cardio-vascular disease. CD59 is a key complement regulatory membrane protein that specifically inhibits formation of the membrane attack complex of complement (MAC), a transmembrane pore that triggers the release of growth factors and cytokines that stimulate cell proliferation, inflammation and thrombosis. Human CD59 is inactivated by glycation because it contains in its active site a glycation motif formed by amino acid residues K41-H44, as determined by NMR analysis of the human CD59 structure and site directed mutagenesis studies. We proposed that glycation-inactivation of CD59 leads first to increased MAC deposition in diabetic tissues and then to increased MAC-induced release of growth factors and cytokines that synergistically with other hyperglycemia induced pathways promote the diverse tissue damage responsible for the vascular complications that characterize human diabetes. Consistent with this hypothesis, glycated CD59 and activated complement proteins including MAC are found in glomeruli, nerves, blood vessels and failed vein grafts from diabetic but not from nondiabetic patients. Importantly, we have shown that a soluble form of CD59, both glycated and non-glycated, can be measured in human urine and plasma by established ELISAs. Glycated CD59 levels seem to correlate with the level of glycemic exposure. These extensive preliminary data make it imperative to assess whether glycated CD59 represents a pathogenically relevant biomarker of diabetic vascular complications. Specifically we will investigate whether glycated CD59 in plasma and/or urine identifies sub-populations at risk of developing vascular complications of diabetes (Specific Aim 1), discriminates persons with impaired glucose tolerance who have a higher risk of cardiovascular disease (Specific Aim 2), and predicts the risk of developing diabetic nephropathy (Specific Aim 3) and/or the risk of vein graft failure after peripheral by-pass surgery (Specific Aim 4). Successful accomplishment of these Specific Aims will provide a novel biomarker of diabetic vascular complications; it will also open new avenues for the early treatment and perhaps prevention of those diabetic complications.