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J. Biol. Chem., Vol. 277, Issue 17, 14370-14378, April 26, 2002

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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^*

R. Brooks Robey^§¶, Jianfei Ma^¶, Anna V. P. Santos^¶, Oscar A. Noboa^¶, Platina E. Coy^¶, and Jane M. Bryson^¶

From the Departments of  Medicine, Section of Nephrology, and ^§ Physiology and Biophysics, University of Illinois at Chicago College of Medicine, Chicago, Illinois 60612 and the ^¶ Veterans Affairs Chicago Health Care System, West Side Division, Chicago, Illinois 60612

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 (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.

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