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Am J Physiol Renal Physiol 281: F151-F162, 2001;
0363-6127/01 $5.00
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Vol. 281, Issue 1, F151-F162, July 2001

Angiotensin II activates the GFAT promoter in mesangial cells

Leighton R. James1, Alistair Ingram2, Hao Ly1, Kerri Thai1, Lu Cai1, and James W. Scholey1

1 Department of Medicine, University of Toronto, Toronto, and 2 Department of Medicine, McMaster University, Hamilton, Ontario M5G 2C4, Canada

Expression of glutamine:fructose-6-phosphate amidotransferase (GFAT), the rate-limiting enzyme for glucose entry into the hexosamine pathway, is transcriptionally regulated. Immunohistochemical studies of human kidney biopsies demonstrate increased GFAT expression in diabetic glomeruli, but the mechanism responsible for this overexpression is unknown. Given the role of ANG II in diabetic kidney disease, we chose to study the effect of ANG II on GFAT promoter activity in mesangial cells (MC). Exposure of MC to ANG II (10-7 M) increased GFAT promoter activity (2.5-fold), mRNA (3-fold), and protein (1.6-fold). ANG II-mediated GFAT promoter activation was inhibited by the ANG II type I receptor antagonist candesartan (10-8 M) but was unaffected by the ANG II type II receptor antagonist PD-123319 (10-8 M). The intracellular calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (10-6 M), protein kinase C (PKC) inhibitors bisindoylmaleimide-4 (10-6 M) and calphostin C (10-7 M), protein tyrosine kinase (PTK) inhibitor genistein (10-4 M), Src family kinase inhibitor PP2 (2.5 × 10-7 M), p42/44 mitogen-activated protein kinase (MAPK) inhibitor PD-98059 (10-5 M), and the epidermal growth factor (EGF) inhibitor AG-1478 all attenuated GFAT promoter activation by ANG II. We conclude that the GFAT promoter is activated by ANG II via the AT1 receptor. Promoter activation is calcium dependent and PKC dependent but also involves PTK signaling pathways including Src, the EGF receptor, and p42/44 MAPK.

angiotensin II; signaling; glomerulus; mesangial cells; glutamine:fructose-6-phosphate amidotransferase


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