title: Preconditioning mice with activators of AMPK ameliorates ischemic acute kidney injury in vivo.
abstract: This study had two objectives: 1) to determine whether preconditioning cultured proximal tubular cells (PTCs) with pharmacological activators of AMP-activated protein kinase (AMPK) protects these cells from apoptosis induced by metabolic stress in vitro and 2) to assess the effects of preconditioning mice with these agents on the severity of ischemic acute renal kidney injury (AKI) in vivo. We demonstrate that preconditioning PTCs with 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) or A-769662 reduces apoptosis of PTCs induced by subsequent stress. We also show that the reduction in cell death during metabolic stress associated with pretreatment by AMPK activators is associated with an increase in the cytosolic level of ATP, which is mediated by an increase in the rate of glycolysis. In addition, we provide evidence that the effect of AMPK activators on glycolysis is mediated, at least in part, by an increased uptake of glucose, and by the induction of hexokinase II (HK II) expression. Our data also show that the increased in HK II expression associated with preconditioning with AMPK activators is mediated by the activation (phosphorylation) of the cAMP-response element binding protein (CREB). We also provide entirely novel evidence that that A-79662 is substantially more effective than AICAR in mediating these alterations in PTCs in vitro. Finally, we demonstrate that preconditioning mice with AICAR or A-769662 substantially reduces the severity of renal dysfunction and tubular injury in a model of ischemic AKI in vivo and that the efficacy of AICAR and A-768662 in ameliorating ischemic AKI in vivo is comparable.
authors.affiliation: Section of Nephrology, Department of Medicine, Stony Brook University Medical Center, Stony Brook, New York; Section of Nephrology, Department of Medicine, Northport Veterans Affairs Hospital, Northport, New York; wilfred.lieberthal@stonybrookmedicine.edu.
authors.forename: Wilfred
authors.initials: W
authors.lastname: Lieberthal
authors.affiliation: Section of Nephrology, Department of Medicine, Stony Brook University Medical Center, Stony Brook, New York.
authors.forename: Meiyi
authors.initials: M
authors.lastname: Tang
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Mark
authors.initials: M
authors.lastname: Lusco
authors.affiliation: Section of Nephrology, Department of Medicine, Stony Brook University Medical Center, Stony Brook, New York.
authors.forename: Mersema
authors.initials: M
authors.lastname: Abate
authors.affiliation: Section of Nephrology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, Illinois; and Section of Nephrology, Department of Medicine, Jesse Brown Veterans Affairs Hospital, Chicago, Illinois.
authors.forename: Jerrold S
authors.initials: JS
authors.lastname: Levine
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D058186:Acute Kidney Injury / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds; D007511:Ischemia / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control*; D019194:Ischemic Preconditioning / Q000379:methods*; D007668:Kidney / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D011753:Pyrones / Q000494:pharmacology / Q000627:therapeutic use; D012265:Ribonucleotides / Q000494:pharmacology / Q000627:therapeutic use*; D013876:Thiophenes / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D001713:Biphenyl Compounds; D020011:Protective Agents; D011753:Pyrones; D012265:Ribonucleotides; D013876:Thiophenes; D000620:Aminoimidazole Carboxamide; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide; C512408:4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile
keywords: AMP-activated protein kinase (AMPK); apoptosis; glycolysis, hexokinases; ischemic AKI