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Divisions of 1 Nephrology and 2 Endocrinology, Department of Medicine, Mount Sinai/University Health Network, University of Toronto, Toronto, Ontario, Canada M5G 2C4
Effects of hyperglycemia on glomerular cells may be
mediated by glucose entry into the hexosamine pathway, and mesangial cell (MC) expression of the hexosamine pathway rate-limiting enzyme glutamine:fructose-6-phosphate amidotransferase (GFAT) is increased in
diabetic glomerulosclerosis. We hypothesized that GFAT activity would
be an important determinant of gene expression in glomerular MC. When
overexpressed in primary MC, GFAT produced a two- to threefold increase
in the activity of plasminogen activator inhibitor-1 (PAI-1) promoter.
There was a 1.4-fold increase in PAI-1 promoter activity in cells
exposed to high glucose (20 mM), whereas in MC overexpressing GFAT,
exposure to high glucose caused a 3.5- to 4-fold increase in promoter
activity. PAI-1 promoter activation was dependent on GFAT enzyme
activity because o-diazoacetyly-L-serine and
6-diazo-5-oxonorleucine, inhibitors of GFAT enzyme
activity, abrogated the activation of PAI-1 promoter in MC
overexpressing GFAT. Glucosamine, which is downstream of GFAT in the
hexosamine pathway, produced a 2.5-fold increase in the PAI-1 promoter
activity. In addition to increasing the mRNA levels for transforming
growth factor-
1 (TGF-1), GFAT overexpression also increased mRNA
levels for the TGF- type I and type II receptors.
TGF--neutralizing antibody did not normalize PAI-1 promoter activity
in MC exposed to glucosamine or those overexpressing GFAT. We conclude
that GFAT expression and activity are important determinants of gene expression in MC and that flux through the hexosamine pathway activates
expression of genes implicated in vascular injury pathways.
glutamine:fructose-6-phosphate amidotransferase; plasminogen activator inhibitor-1; diabetic nephropathy; gene expression
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