A role for AMP-activated protein kinase in diabetes-induced renal hypertrophy

Am J Physiol Renal Physiol. 2007 Feb;292(2):F617-27. doi: 10.1152/ajprenal.00278.2006. Epub 2006 Oct 3.

Abstract

We tested the hypothesis that AMP-activated protein kinase (AMPK), an energy sensor, regulates diabetes-induced renal hypertrophy. In kidney glomerular epithelial cells, high glucose (30 mM), but not equimolar mannitol, stimulated de novo protein synthesis and induced hypertrophy in association with increased phosphorylation of eukaryotic initiation factor 4E binding protein 1 and decreased phosphorylation of eukaryotic elongation factor 2, regulatory events in mRNA translation. These high-glucose-induced changes in protein synthesis were phosphatidylinositol 3-kinase, Akt, and mammalian target of rapamycin (mTOR) dependent and transforming growth factor-beta independent. High glucose reduced AMPK alpha-subunit theronine (Thr) 172 phosphorylation, which required Akt activation. Changes in AMP and ATP content could not fully account for high-glucose-induced reductions in AMPK phosphorylation. Metformin and 5-aminoimidazole-4-carboxamide-1beta-riboside (AICAR) increased AMPK phosphorylation, inhibited high-glucose stimulation of protein synthesis, and prevented high-glucose-induced changes in phosphorylation of 4E binding protein 1 and eukaryotic elongation factor 2. Expression of kinase-inactive AMPK further increased high-glucose-induced protein synthesis. Renal hypertrophy in rats with Type 1 diabetes was associated with reduction in AMPK phosphorylation and increased mTOR activity. In diabetic rats, metformin and AICAR increased renal AMPK phosphorylation, reversed mTOR activation, and inhibited renal hypertrophy, without affecting hyperglycemia. AMPK is a newly identified regulator of renal hypertrophy in diabetes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • AMP-Activated Protein Kinases
  • Aminoimidazole Carboxamide / analogs & derivatives
  • Aminoimidazole Carboxamide / pharmacology
  • Animals
  • Carrier Proteins / metabolism
  • Cells, Cultured
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Type 1 / metabolism
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetic Nephropathies / physiopathology*
  • Glucose / pharmacology
  • Hypertrophy / metabolism
  • Intracellular Signaling Peptides and Proteins
  • Kidney / pathology*
  • Metformin / pharmacology
  • Multienzyme Complexes / physiology*
  • Phosphoproteins / metabolism
  • Protein-Serine-Threonine Kinases / physiology*
  • Rats
  • Ribonucleosides / pharmacology
  • Transforming Growth Factor beta / pharmacology

Substances

  • Carrier Proteins
  • Eif4ebp1 protein, rat
  • Intracellular Signaling Peptides and Proteins
  • Multienzyme Complexes
  • Phosphoproteins
  • Ribonucleosides
  • Transforming Growth Factor beta
  • Aminoimidazole Carboxamide
  • acadesine
  • Metformin
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases
  • Glucose