The Role of O-GlcNAcylation in Diabetic Nephropathy

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 DESCRIPTION (provided by applicant): Diabetic nephropathy (DN) is the leading cause of chronic kidney disease and one of the most significant long-term complications in terms of morbidity and mortality for individuals with diabetes. Several ultrastructural changes occur in the glomeruli of a diabetic patient, such as glomerular hyperfiltration, mesangial expansion as a result of accumulation of the extracellular matrix components, and podocyte apoptosis. While the specific mechanisms underlying the development of DN remain unknown, hyperglycemia is considered an important contributing factor in the development and the progression of this disease. Changes in glucose metabolism have been shown to initiate ultrastructural changes by stimulating flux through the hexosamine biosynthetic pathway. The major endpoint for the hexosamine biosynthetic pathway is the formation of UDP-GlcNAc, which is a substrate for O-GlcNAc transferase (OGT) and glycosaminoglycan (GAG) synthesis. Heparan sulfate proteoglycans (HSPGs), part of the glomerular basement membrane (GBM), are thought to have an important role in the maintenance of the charge selective filtration barrier and the organizational maintenance of the GBM constituents. Podocytes are thought to work together with the GBM to function as a dynamic barrier to protein loss. The loss of proteoglycans in the GBM has been recently questioned as causative of the proteinuria and current research has focused on the podocyte as a central target for the effects of the metabolic milieu in the development and progression of diabetic proteinuria. It has been shown that several proteins, such as podocyte cytoskeletal protein a-actinin 4 [22], and transcription factors, such Sp1 and FOXO-1, are O-GlcNAcylated. These modifications may alter the function of proteins and the promoter specificity. Thus, we sought to characterize the direct roles of O-GlcNAc in kidney disease associated with diabetes by: 1) elucidating effects of O-GlcNAcylation on ECM protein and proteoglycan (PG) gene expression utilizing qPCR arrays, 2) examining whether O-GlcNAcylation contributes to hyperfiltration by altering the expression, biosynthesis, or cleavage of HSPGs in a hyperglycemic environment, and 3) defining the role of O-GlcNAcylation in the nephrobiology of renal disorders in a type-2 diabetes transgenic model of tamoxifen-inducible podocyte specific knockout of O-GlcNAc transferase (OGT), leading to specific OGT KO in podocytes.