Regulation of mesangial cell hexokinase activity and expression by heparin-binding epidermal growth factor-like growth factor: epidermal growth factors and phorbol esters increase glucose metabolism via a common mechanism involving classic mitogen-activated protein kinase pathway activation and induction of hexokinase II expression.
Heparin-binding epidermal growth factor -like growth factor (HB-EGF) expression and hexokinase (HK) activity are increased in various pathologic renal conditions. Although the mitogenic properties of HB-EGF have been well characterized, its effects on glucose (Glc) metabolism have not. We therefore examined the possibility that HB-EGF might regulate HK activity and expression in glomerular mesangial cells, which constitute the principal renal cell type affected by a variety of pathologic conditions. Protein kinase C (PKC)-dependent classic mitogen-activated protein kinase (MAPK) pathway activation has been associated with increased HK activity in this cell type, so we also examined dependence upon these signaling intermediates. HB-EGF (> or =10 nm) increased total HK activity over 50% within 12-24 h, an effect mimicked by other EGF receptor agonists, but not by IGF-1 or elevated Glc. EGF receptor and classic MAPK pathway antagonists prevented this increase, as did general inhibitors of gene transcription and protein synthesis. Both HB-EGF and phorbol esters activated the classic MAPK pathway, albeit via PKC-independent and PKC-dependent mechanisms, respectively. Both stimuli were associated with increased HK activity, selectively increased HKII isoform expression, and increased Glc metabolism via both the glycolytic-tricarboxylic acid cycle route and the pentose phosphate pathway. HB-EGF thus constitutes a novel regulator of mesangial cell HK activity and Glc metabolism. HKII is the principal regulated isoform in these cells, as it is in insulin-sensitive peripheral tissues, such as muscle. However, the uniform requirement for classic MAPK pathway activation distinguishes HKII regulation in mesangial cells from that observed in muscle. These findings suggest a novel mechanism whereby growth factors may couple metabolism to glomerular injury.
Robey
R Brooks
RB
Department of Medicine, University of Illinois at Chicago College of Medicine, Chicago, Illinois 60612, USA. RBRobey@uic.edu
Ma
Jianfei
J
Santos
Anna V P
AV
Noboa
Oscar A
OA
Coy
Platina E
PE
Bryson
Jane M
JM
D000818:Animals; D002460:Cell Line; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000502:physiology*; D005419:Flavonoids / Q000494:pharmacology; D005920:Glomerular Mesangium / Q000201:enzymology*; D005947:Glucose / Q000378:metabolism*; D066257:Heparin-binding EGF-like Growth Factor; D006593:Hexokinase / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D020935:MAP Kinase Signaling System; D051379:Mice; D010084:Oxidation-Reduction; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014443:Tyrosine / Q000378:metabolism
D004791:Enzyme Inhibitors; D005419:Flavonoids; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D007527:Isoenzymes; D008024:Ligands; D014443:Tyrosine; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; D006593:Hexokinase; D011493:Protein Kinase C; D005947:Glucose; D013755:Tetradecanoylphorbol Acetate; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one