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Department of Medicine (H.J.G., C.I.W., I.G.F.), Mount Sinai Hospital and University Health Network, Toronto, Ontario, Canada M5G 1X5; Banting and Best Diabetes Centre (H.J.G., C.I.W., I.G.F.), Toronto, Ontario, Canada M5G 2C4; Department of Physiology (I.G.F.), University of Toronto, Toronto, Ontario, Canada M5S 1A8; and Department of Biological Chemistry (G.W.H.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2185
Address all correspondence and requests for reprints to: Dr. I. George Fantus, Department of Medicine, Mount Sinai Hospital, 600 University Avenue, Lebovic Building, Room 5-028, Toronto, Ontario, Canada M5G 1X5. E-mail: fantus{at}mshri.on.ca.
Metabolic flux through the hexosamine biosynthetic pathway (HBP) is increased in the presence of high glucose (HG) and potentially stimulates the expression of genes associated with the development of diabetic nephropathy. A number of synthetic processes are coupled to the HBP, including enzymatic intracellular O-glycosylation (O-GlcNAcylation), the addition of single O-linked N-acetylglucosamine monosaccharides to serine or threonine residues. Despite much data linking flow through the HBP and gene expression, the exact contribution of O-GlcNAcylation to HG-stimulated gene expression remains unclear. In glomerular mesangial cells, HG-stimulated plasminogen activator inhibitor-1 (PAI-1) gene expression requires the HBP and the transcription factor, Sp1. In this study, the specific role of O-GlcNAcylation in HG-induced PAI-1 expression was tested by limiting this modification with a dominant-negative O-linked N-acetylglucosamine transferase, by overexpression of neutral ß-N-acetylglucosaminidase, and by knockdown of O-linked ß-N-acetylglucosamine transferase expression by RNA interference. Decreasing O-GlcNAcylation by these means inhibited the ability of HG to increase endogenous PAI-1 mRNA and protein levels, the activity of a PAI-1 promoter-luciferase reporter gene, and Sp1 transcriptional activation. Conversely, treatment with the ß-N-acetylglucosaminidase inhibitor, O-(2-acetamido-2-deoxy-D-glucopyranosylidene)amino-N-phenylcarbamate, in the presence of normal glucose increased Sp1 O-GlcNAcylation and PAI-1 mRNA and protein levels. These findings demonstrate for the first time that among the pathways served by the HBP, O-GlcNAcylation, is obligatory for HG-induced PAI-1 gene expression and Sp1 transcriptional activation in mesangial cells.
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