Regulation of glucose transporter (GLUT1) gene expression by angiotensin II in mesangial cells: involvement of HB-EGF and EGF receptor transactivation.
In the development of diabetic nephropathy, angiotensin (Ang) II is thought to exert numerous actions on the glomerulus, and especially on the mesangium. However, the role(s) played by Ang II in the glucose metabolism per se in mesangial cells remains unclear. Ang II, at least via its type 1 receptor (AT1-R)-mediated effect, phosphorylates extracellular signal regulated kinase (ERK) by transactivation of epidermal growth factor receptors (EGF-Rs) via the Ca2+ or protein kinase C (PKC) pathways. Our objective in the present study was to assess the effect of Ang II on glucose transporter 1 (GLUT1) gene expression and to clarify the involvement of EGF-R in Ang II-mediated GLUT1 mRNA expression in glomerular mesangial cells. The results showed that Ang II upregulated GLUT1 mRNA accumulation in a time- and dose-dependent manner (peaking at 12 h; approximately 3.8-fold vs. control), and this upregulation was completely inhibited by the PKC inhibitor calphostin-C. The Ang Il-induced GLUT1 expression was significantly inhibited by the EGF-R inhibitor AG1478 (approximately 80% inhibition), by inactivation of ERK by PD98059, and by pretreatment with heparin and the metalloproteinase (MMP) inhibitor batimastat. On the other hand, phorbol ester markedly upregulated GLUT1 mRNA (approximately 8.6-fold). Batimostat and AG1478 significantly reduced the phorbol ester-induced GLUT1 mRNA expression (approximately 72 and approximately 69% inhibition, respectively). In conclusion, PKC-mediated heparin-binding (HB)-EGF/EGF transactivation followed by ERK activation plays a predominant role in the induction of GLUT1 expression by Ang II.
Nose
Atsuko
A
Department of Medicine II, Kansai Medical University, Moriguchi, Japan.
Mori
Yasukiyo
Y
Uchiyama-Tanaka
Yoko
Y
Kishimoto
Noriko
N
Maruyama
Katsuya
K
Matsubara
Hiroaki
H
Iwasaka
Toshiji
T
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002273:Carcinogens / Q000494:pharmacology; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D005920:Glomerular Mesangium / Q000166:cytology / Q000378:metabolism*; D051272:Glucose Transporter Type 1; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009004:Monosaccharide Transport Proteins / Q000235:genetics*; D010703:Phorbol Esters / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015854:Up-Regulation; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D002273:Carcinogens; D051272:Glucose Transporter Type 1; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D009004:Monosaccharide Transport Proteins; D010703:Phorbol Esters; D012333:RNA, Messenger; C495678:Slc2a1 protein, mouse; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D011493:Protein Kinase C; D002118:Calcium