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Abstract Phorbol esters increase glucose (Glc) uptake and utilization in a variety of cell types, and, in some cells, these changes have been attributed to increased Glc phosphorylation and better functional coupling of hexokinases (HKs) to facilitative Glc transporters. Phorbol esters are potent mesangial cell mitogens, but their effects on HK-catalyzed Glc phosphorylation and metabolism are unknown. When examined in murine mesangial cells, active, but not inactive, phorbol esters increased HK activity in a time- and dose-dependent manner. Maximal induction of HK activity at 12–24 h was accompanied by parallel increases in both Glc utilization and lactate production and was blocked by the specific MEK1/2 inhibitor PD-98059 (IC 50 ∼3 μM). This effect involved early activation of protein kinase C (PKC), MEK1/2, and ERK1/2, and the prolonged time course of subsequent HK induction was attributable, in part, to requirements for ongoing gene transcription and de novo protein synthesis. Mesangial cell HK activity thus exhibits novel regulatory behavior involving both PKC and classic MAPK pathway activation, suggesting specific mechanisms whereby PKC activation may influence Glc metabolism. glomerular mesangial cells hexokinase protein kinase C MEK1/2 ERK1/2 mitogen-activated protein kinase Footnotes Address for reprint requests and other correspondence: R. B. Robey, Dept. of Medicine, Section of Nephrology (M/C 793), 820 South Wood St., Rm. 418W CSN, Chicago, IL 60612-7315 (E-mail: RBRobey@uic.edu ). Portions of this work were presented in preliminary form at the 30th Annual Meeting of the American Society of Nephrology in San Antonio, TX, November 4, 1997, and at the 10th International Conference on Second Messengers and Phosphoproteins in Jerusalem, Israel, November 9, 1998. This work was supported, in part, by Grants-in-Aid from the National Kidney Foundation of Illinois (to R. B. Robey) and the American Heart Association of Metropolitan Chicago (to R. B. Robey), as well as by a Department of Veterans Affairs Merit Review Award (to R. B. Robey). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “ advertisement ” in accordance with 18 U.S.C. §1734 solely to indicate this fact. Copyright © 1999 the American Physiological Society
AJP - Renal Physiology – The American Physiological Society
Published: Nov 1, 1999
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