Angiotensin II activates the GFAT promoter in mesangial cells

Citation
Lr. James et al., Angiotensin II activates the GFAT promoter in mesangial cells, AM J P-REN, 281(1), 2001, pp. F151-F162
Citations number
71
Categorie Soggetti
da verificare
Journal title
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
ISSN journal
03636127 → ACNP
Volume
281
Issue
1
Year of publication
2001
Pages
F151 - F162
Database
ISI
SICI code
0363-6127(200107)281:1<F151:AIATGP>2.0.ZU;2-F
Abstract
Expression of glutamine:fructose-6-phosphate amidotransferase (GFAT), the r ate-limiting enzyme for glucose entry into the hexosamine pathway, is trans criptionally regulated. Immunohistochemical studies of human kidney biopsie s demonstrate increased GFAT expression in diabetic glomeruli, but the mech anism 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 G FAT 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 pro tein (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 unaff ected by the ANG II type II receptor antagonist PD-123319 (10(-8) M). The i ntracellular calcium chelator 1,2-bis(2-aminophenoxy)ethaneN,N,N',N'-tetraa cetic acid (10(-6) M), protein kinase C (PKC) inhibitors bisindoylmaleimide -4 (10(-6) M) and calphostin C (10(-7) M), protein tyrosine kinase (PTK) in hibitor genistein (10(-4) M), Src family kinase inhibitor PP2 (2.5 x 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 attenua ted GFAT promoter activation by ANG II. We conclude that the GFAT promoter is activated by ANG II via the AT(1) receptor. Promoter activation is calci um dependent and PKC dependent but also involves PTK signaling pathways inc luding Src, the EGF receptor, and p42/44 MAPK.