Regulation of Glucose Transporter (GLUT1) Gene Expression by Angiotensin II in Mesangial Cells: Involvement of HB-EGF and EGF Receptor Transactivation.
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<B>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 <I>per se</I> in mesangial cells remains unclear. Ang II, at least <I>via</I> its type 1 receptor (AT1-R)-mediated effect, phosphorylates extracellular signal regulated kinase (ERK) by transactivation of epidermal growth factor receptors (EGF-Rs) <I>via</I> the Ca<SUP>2+</SUP> or protein kinase C (PKC) pathways. Our objective in the present study was to assess the effect of Ang II on glucose transporter 1 (<I>GLUT1</I>) gene expression and to clarify the involvement of EGF-R in Ang II-mediated <I>GLUT1</I> mRNA expression in glomerular mesangial cells. The results showed that Ang II upregulated <I>GLUT1</I> mRNA accumulation in a time- and dose-dependent manner (peaking at 12 h; ～3.8-fold <I>vs.</I> control), and this upregulation was completely inhibited by the PKC inhibitor calphostin-C. The Ang II-induced <I>GLUT1</I> expression was significantly inhibited by the EGF-R inhibitor AG1478 (～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 <I>GLUT1</I> mRNA (～8.6-fold). Batimostat and AG1478 significantly reduced the phorbol ester-induced <I>GLUT1</I> mRNA expression (～72 and ～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 <I>GLUT1</I> expression by Ang II. (<I>Hypertens Res</I> 2003; 26: 67-73)</B>
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日本高血圧学会 | 論文
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