title: Roles of AMP-activated protein kinase in diabetes-induced retinal inflammation.
abstract: OBJECTIVE
  AMP-activated protein kinase (AMPK) is a sensor of cellular energy status. The purpose of the present study was to elucidate the roles of AMPK in the pathogenesis of diabetic retinopathy using the known AMPK activators resveratrol and AICAR (5-aminoimidazole-4-carboxamide ribonucleoside) in a mouse model.
  
  
  METHODS
  C57BL/6 mice with streptozotocin-induced diabetes were treated with resveratrol orally at 50 mg/kg for 7 days or with AICAR intraperitoneally at 100 mg/kg 24 hours before death. Retinal protein levels of phosphorylated and total AMPK, phosphorylated nuclear factor (NF)-κB p65, intercellular adhesion molecule (ICAM)-1, and vascular endothelial growth factor (VEGF) were evaluated by Western blot analysis or enzyme-linked immunosorbent assay. Retinal activity of sirtuin (SIRT)1 was measured by deacetylase fluorometric assay. Leukocyte adhesion to the retinal vasculature was examined with a concanavalin A lectin perfusion-labeling technique.
  
  
  RESULTS
  Induction of diabetes in mice led to retinal AMPK dephosphorylation, which was significantly reversed by either resveratrol or AICAR. Either resveratrol or AICAR significantly reversed SIRT1 deactivation and NF-κB phosphorylation, both of which were induced in the diabetic retina. Administration of resveratrol to diabetic mice significantly reduced diabetes-induced retinal leukocyte adhesion, together with retinal expression of ICAM-1 and VEGF.
  
  
  CONCLUSIONS
  The present findings reveal that diabetes-induced retinal inflammation stems from downregulation of the AMPK pathway, leading subsequently to SIRT1 deactivation and NF-κB activation. The data also suggest the potential use of the AMPK activator resveratrol as a therapeutic agent for diabetic retinopathy.
authors: Laboratory of Retinal Cell Biology, Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.
authors: Shunsuke
authors: S
authors: Kubota
authors: Yoko
authors: Y
authors: Ozawa
authors: Toshihide
authors: T
authors: Kurihara
authors: Mariko
authors: M
authors: Sasaki
authors: Kenya
authors: K
authors: Yuki
authors: Seiji
authors: S
authors: Miyake
authors: Kousuke
authors: K
authors: Noda
authors: Susumu
authors: S
authors: Ishida
authors: Kazuo
authors: K
authors: Tsubota
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology*; D000284:Administration, Oral; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000627:therapeutic use; D000818:Animals; D015153:Blotting, Western; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology* / Q000517:prevention & control; D003930:Diabetic Retinopathy / Q000201:enzymology* / Q000517:prevention & control; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D007249:Inflammation / Q000201:enzymology / Q000517:prevention & control; D007274:Injections, Intraperitoneal; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D000077185:Resveratrol; D012173:Retinitis / Q000201:enzymology* / Q000517:prevention & control; D012265:Ribonucleotides / Q000627:therapeutic use; D056564:Sirtuin 1 / Q000378:metabolism; D013267:Stilbenes / Q000627:therapeutic use; D051996:Transcription Factor RelA / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D012265:Ribonucleotides; D013267:Stilbenes; D051996:Transcription Factor RelA; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D018799:Intercellular Adhesion Molecule-1; D000620:Aminoimidazole Carboxamide; D055372:AMP-Activated Protein Kinases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; C031143:AICA ribonucleotide; D000077185:Resveratrol