Regulation of elongation phase of mRNA translation in diabetic nephropathy: amelioration by rapamycin.
High glucose and high insulin, pathogenic factors in type 2 diabetes, induce rapid synthesis of the matrix protein laminin-beta1 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-beta1 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-beta1 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-beta1 protein content, without affecting hyperglycemia. These data show that mTOR is an attractive target for amelioration of diabetes-induced renal injury.
Sataranatarajan
Kavithalakshmi
K
O'Brien Kidney Research Center, Department of Medicine, MC 7882, University of Texas Health Science Center, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900, USA.
Mariappan
Meenalakshmi M
MM
Lee
Myung Ja
MJ
Feliers
Denis
D
Choudhury
Goutam Ghosh
GG
Barnes
Jeffrey L
JL
Kasinath
Balakuntalam S
BS
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology* / Q000235:genetics; D003928:Diabetic Nephropathies / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D054736:Elongation Factor 2 Kinase / Q000378:metabolism; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D007672:Kidney Cortex / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D007797:Laminin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000187:drug effects*; D011494:Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases
D007328:Insulin; C513277:Lamb1 protein, mouse; D007797:Laminin; D011494:Protein Kinases; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; C517690:Eef2k protein, mouse; D054736:Elongation Factor 2 Kinase; D005947:Glucose; D020123:Sirolimus