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 Choudhury, Balakuntalam S. Kasinath

Research output: Contribution to journalArticle

52 Scopus citations

Abstract

High glucose (30 mM) and high insulin (1 nM), pathogenic factors of type 2 diabetes, increased mRNA expression and synthesis of laminin β1 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 eIF2Bε. 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 eIF2Bε 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 eIF2Bε, which correlated with renal hypertrophy at 2 weeks, and increased laminin β1 and fibronectin protein content at 2 months. GSK3β and eIF2Bε 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.

Original languageEnglish (US)
Pages (from-to)30566-30575
Number of pages10
JournalJournal of Biological Chemistry
Volume283
Issue number45
DOIs
StatePublished - Nov 7 2008

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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