Overexpression of glutamine : fructose-6-phosphate-amidotransferase induces transforming growth factor-beta 1 synthesis in NIH-3T3 fibroblasts

Increased flux through the hexosamine biosynthetic pathway with glutamine:f ructose-6-phosphate-amidotransferase (GFAT) as rate-limiting enzyme has bee n linked to the enhanced bioactivity of the prosclerotic cytokine transform ing growth factor beta1 (TGF-beta1) in fibrotic complications, particularly in diabetic kidney disease. Here, we investigate in a stable transfection system the effect of overexpression of GFAT on TGF-beta1 synthesis in NIH-3 T3 fibroblasts. We demonstrate a 1.8-fold stimulation of TGF-beta1 mRNA and a 1.9-fold increased protein expression, whereas TGF-beta2 production was not upregulated. The 1.5-fold enhanced TGF-beta1 promoter activity suggests a transcriptional regulation, The elevated TGF-beta1 protein is biological ly active since GFAT-overexpressing cells exhibit a 2-fold fibronectin prod uction. The results indicate a GFAT-dependent induction of TGF-beta1 synthe sis. (C) 2001 Federation of European Biochemical Societies. Published by El sevier Science B.V. All rights reserved.