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A more recent version of this article appeared on December 1, 2007

Published online before print November 8, 2007
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Copyright © 2007 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2007.070412

Accepted for publication August 30, 2007.

Article

Regulation of Elongation Phase of mRNA Translation in Diabetic Nephropathy. Amelioration by Rapamycin

Kavithalakshmi Sataranatarajan*, Meenalakshmi M. Mariappan*, Myung Ja Lee*, Denis Feliers*, Goutam Ghosh Choudhury*{dagger}, Jeffrey L. Barnes*{dagger}, and Balakuntalam S. Kasinath*{dagger}@

From the O'Brien Kidney Research Center, Department of Medicine,* University of Texas Health Science Center, San Antonio; and the South Texas Veterans Health Care System,{dagger} San Antonio, Texas

@ To whom correspondence should be addressed. E-mail: kasinath{at}uthscsa.edu.


  Abstract

High glucose and high insulin, pathogenic factors in type 2 diabetes, induce rapid synthesis of the matrix protein laminin-{beta}1 in renal proximal tubular epithelial cells by stimulation of initiation phase of mRNA translation. We investigated if elongation phase of translation also contributes to high glucose and high insulin induction of laminin-{beta}1 synthesis in proximal tubular epithelial cells. High glucose or high insulin rapidly increased activating Thr56 dephosphorylation of eEF2 and inactivating Ser366 phosphorylation of eEF2 kinase, events that facilitate elongation. Studies with inhibitors showed that PI3 kinase-Akt-mTOR-p70S6 kinase pathway controlled changes in phosphorylation of eEF2 and eEF2 kinase induced by high glucose or high insulin. Renal cortical homogenates from db/db mice in early stage of type 2 diabetes showed decrease in eEF2 phosphorylation and increment in eEF2 kinase phosphorylation in association with renal hypertrophy and glomerular and tubular increase in laminin-{beta}1 content. Rapamycin, an inhibitor of mTOR, abolished diabetes-induced changes in phosphorylation of eEF2, eEF2 kinase, and p70S6 kinase and ameliorated renal hypertrophy and laminin-{beta}1 protein content, without affecting hyperglycemia. These data show that mTOR is an attractive target for amelioration of diabetes-induced renal injury.




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