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J. Biol. Chem., Vol. 283, Issue 45, 30566-30575, November 7, 2008

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Glycogen Synthase Kinase 3β Is a Novel Regulator of High Glucose- and High Insulin-induced Extracellular Matrix Protein Synthesis in Renal Proximal Tubular Epithelial Cells^*

Meenalakshmi M. Mariappan, Megan Shetty, Kavithalakshmi Sataranatarajan, Goutam Ghosh Choudhury¹, and Balakuntalam S. Kasinath²

From the O'Brien Kidney Research Center, Division of Nephrology, Department of Medicine, The University of Texas Health Science Center, San Antonio, Texas 78229 and the South Texas Veterans Health Care System, San Antonio, Texas 78229

High glucose (30 mM) and high insulin (1 nM), pathogenic factors of type 2 diabetes, increased mRNA expression and synthesis of lamininβ1 and fibronectin after 24 h of incubation in kidney proximal tubular epithelial (MCT) cells. We tested the hypothesis that inactivation of glycogen synthase kinase 3β (GSK3β) by high glucose and high insulin induces increase in synthesis of laminin β1 via activation of eIF2B. Both high glucose and high insulin induced Ser-9 phosphorylation and inactivation of GSK3β at 2 h that lasted for up to 48 h. This was associated with dephosphorylation of eIF2B and eEF2, and increase in phosphorylation of 4E-BP1 and eIF4E. Expression of the kinase-dead mutant of GSK3β or constitutively active kinase led to increased and diminished laminin β1 synthesis, respectively. Incubation with selective kinase inhibitors showed that high glucose- and high insulin-induced laminin β1 synthesis and phosphorylation of GSK3β were dependent on PI 3-kinase, Erk, and mTOR. High glucose and high insulin augmented activation of Akt, Erk, and p70S6 kinase. Dominant negative Akt, but not dominant negative p70S6 kinase, inhibited GSK3β phosphorylation induced by high glucose and high insulin, suggesting Akt but not p70S6 kinase was upstream of GSK3β. Status of GSK3β was examined in vivo in renal cortex of db/db mice with type 2 diabetes at 2 weeks and 2 months of diabetes. Diabetic mice showed increased phosphorylation of renal cortical GSK3β and decreased phosphorylation of eIF2B, which correlated with renal hypertrophy at 2 weeks, and increased laminin β1 and fibronectin protein content at 2 months. GSK3β and eIF2B play a role in augmented protein synthesis associated with high glucose- and high insulin-stimulated hypertrophy and matrix accumulation in renal disease in type 2 diabetes.

Received for publication, March 4, 2008 , and in revised form, July 29, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants DK061597 and DK077295 (to B. S. K.) and DK050190 (to G. G. C.). These studies were also supported by Juvenile Diabetes Research Foundation Grants 3-2007-245 (to M. M. M. and B. S. K.) and 1-2008-185 (to G. G. C.), American Diabetes Association Grant 7-05-RA-60 (to B. S. K.), the Veterans Administration Research Service (to B. S. K. and G. G. C.), and American Heart Association Grant SDG 0630283N (to D. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S6.

¹ A recipient of the Veterans Administration Research Career Scientist Award.

² To whom correspondence should be addressed: Dept. of Medicine MC7882, University of Texas Health Science Center, 7703 Floyd Curl Dr., San Antonio TX 78229-3900. Tel.: 210-567-4707; Fax: 210-567-4712; E-mail: Kasinath{at}uthscsa.edu.

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