Overexpression of glutamine:fructose‐6‐phosphate‐amidotransferase induces transforming growth factor‐β1 synthesis in NIH‐3T3 fibroblasts

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Abstract
Increased flux through the hexosamine biosynthetic pathway with glutamine:fructose‐6‐phosphate‐amidotransferase (GFAT) as rate‐limiting enzyme has been linked to the enhanced bioactivity of the prosclerotic cytokine transforming growth factor β1 (TGF‐β1) in fibrotic complications, particularly in diabetic kidney disease. Here, we investigate in a stable transfection system the effect of overexpression of GFAT on TGF‐β1 synthesis in NIH‐3T3 fibroblasts. We demonstrate a 1.8‐fold stimulation of TGF‐β1 mRNA and a 1.9‐fold increased protein expression, whereas TGF‐β2 production was not upregulated. The 1.5‐fold enhanced TGF‐β1 promoter activity suggests a transcriptional regulation. The elevated TGF‐β1 protein is biologically active since GFAT‐overexpressing cells exhibit a 2‐fold fibronectin production. The results indicate a GFAT‐dependent induction of TGF‐β1 synthesis.

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