title: A role for AMP-activated protein kinase in diabetes-induced renal hypertrophy.
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.
authors.affiliation: Dept. of Nephrology, University of Texas Health Science Center, San Antonio, TX 78229, USA.
authors.forename: Myung-Ja
authors.initials: MJ
authors.lastname: Lee
authors.forename: Denis
authors.initials: D
authors.lastname: Feliers
authors.forename: Meenalakshmi M
authors.initials: MM
authors.lastname: Mariappan
authors.forename: Kavithalakshmi
authors.initials: K
authors.lastname: Sataranatarajan
authors.forename: Lenin
authors.initials: L
authors.lastname: Mahimainathan
authors.forename: Nicolas
authors.initials: N
authors.lastname: Musi
authors.forename: Marc
authors.initials: M
authors.lastname: Foretz
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.forename: Joel M
authors.initials: JM
authors.lastname: Weinberg
authors.forename: Goutam Ghosh
authors.initials: GG
authors.lastname: Choudhury
authors.forename: Balakuntalam S
authors.initials: BS
authors.lastname: Kasinath
mesh_terms: D055372:AMP-Activated Protein Kinases; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000503:physiopathology*; D005947:Glucose / Q000494:pharmacology; D006984:Hypertrophy / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D007668:Kidney / Q000473:pathology*; D008687:Metformin / Q000494:pharmacology; D009097:Multienzyme Complexes / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D051381:Rats; D012263:Ribonucleosides / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D002352:Carrier Proteins; C499526:Eif4ebp1 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D009097:Multienzyme Complexes; D010750:Phosphoproteins; D012263:Ribonucleosides; D016212:Transforming Growth Factor beta; D000620:Aminoimidazole Carboxamide; C011651:acadesine; D008687:Metformin; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose