Regulation of elongation phase of mRNA translation in diabetic nephropathy: Amelioration by rapamycin

Kavithalakshmi Sataranatarajan, Meenalakshmi M. Mariappan, Ja Lee Myung, Denis Feliers, Goutam Ghosh-choudhury, Jeffrey L. Barnes, Balakuntalam S Kasinath

Research output: Contribution to journalArticle

93 Citations (Scopus)

Abstract

High glucose and high insulin, pathogenic factors in type 2 diabetes, induce rapid synthesis of the matrix protein laminin-β1 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-β1 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-β1 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-β1 protein content, without affecting hyperglycemia. These data show that mTOR is an attractive target for amelioration of diabetes-induced renal injury.

Original languageEnglish (US)
Pages (from-to)1733-1742
Number of pages10
JournalAmerican Journal of Pathology
Volume171
Issue number6
DOIs
StatePublished - Dec 2007

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Diabetic Nephropathies
Protein Biosynthesis
Sirolimus
Phosphotransferases
Phosphorylation
Kidney
Insulin
Glucose
Type 2 Diabetes Mellitus
Hypertrophy
Epithelial Cells
Phosphatidylinositol 3-Kinases
Hyperglycemia
Proteins
laminin 1
Wounds and Injuries

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Sataranatarajan, K., Mariappan, M. M., Myung, J. L., Feliers, D., Ghosh-choudhury, G., Barnes, J. L., & Kasinath, B. S. (2007). Regulation of elongation phase of mRNA translation in diabetic nephropathy: Amelioration by rapamycin. American Journal of Pathology, 171(6), 1733-1742. https://doi.org/10.2353/ajpath.2007.070412

Regulation of elongation phase of mRNA translation in diabetic nephropathy : Amelioration by rapamycin. / Sataranatarajan, Kavithalakshmi; Mariappan, Meenalakshmi M.; Myung, Ja Lee; Feliers, Denis; Ghosh-choudhury, Goutam; Barnes, Jeffrey L.; Kasinath, Balakuntalam S.

In: American Journal of Pathology, Vol. 171, No. 6, 12.2007, p. 1733-1742.

Research output: Contribution to journalArticle

Sataranatarajan, K, Mariappan, MM, Myung, JL, Feliers, D, Ghosh-choudhury, G, Barnes, JL & Kasinath, BS 2007, 'Regulation of elongation phase of mRNA translation in diabetic nephropathy: Amelioration by rapamycin', American Journal of Pathology, vol. 171, no. 6, pp. 1733-1742. https://doi.org/10.2353/ajpath.2007.070412
Sataranatarajan, Kavithalakshmi ; Mariappan, Meenalakshmi M. ; Myung, Ja Lee ; Feliers, Denis ; Ghosh-choudhury, Goutam ; Barnes, Jeffrey L. ; Kasinath, Balakuntalam S. / Regulation of elongation phase of mRNA translation in diabetic nephropathy : Amelioration by rapamycin. In: American Journal of Pathology. 2007 ; Vol. 171, No. 6. pp. 1733-1742.
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