title: The involvement of phosphatidylinositol 3-kinase /Akt signaling in high glucose-induced downregulation of GLUT-1 expression in ARPE cells.
abstract: Glucose transporters have been reported to be associated with the development of diabetic retinopathy. Retinal pigment epithelial cells (RPEs) are believed to play an important role in the pathogenesis of diabetic retinopathy. However, the effect of hyperglycemia on glucose transporters in RPEs and the related signal pathways have not yet been elucidated. Therefore, we examined the effect of high glucose on the glucose transporter 1 in ARPEs and the related signal molecules. In the present study, high glucose decreased 2-deoxyglucose uptake in a time (>2 h) and dose dependent manner. In addition, we found that high glucose downregulated the expression of glucose transporter 1 (GLUT-1). The high glucose-induced downregulation of GLUT-1 was blocked by Wortmanin, LY 294002 (PI-3 kinase inhibitors) and Akt (Akt inhibitor). The high glucose increased stimulation of Akt activation in a time dependent manner. We also investigated the upstream regulator of Akt activation. The high glucose-induced phosphorylation of Akt was blocked by bisindolymaleimide I, H-7, staurosporine (protein kinase C [PKC] inhibitors), vitamin C and catalase (antioxidants). In addition, the high glucose-induced downregulation of GLUT-1 was also blocked by PKC inhibitors and antioxidants. Moreover, high glucose increased lipid peroxide formation, which was prevented by PKC inhibitors. In conclusion, high glucose downregulated GLUT-1 by Akt pathway activation mediated by the PKC-oxidative stress signaling pathway in ARPE cells.
authors.affiliation: Bio-therapy Human Resources Center, Department of Veterinary Physiology, College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, South Korea.
authors.forename: Dong-Il
authors.initials: DI
authors.lastname: Kim
authors.forename: Sul-Ki
authors.initials: SK
authors.lastname: Lim
authors.forename: Min-Jung
authors.initials: MJ
authors.lastname: Park
authors.forename: Ho-Jae
authors.initials: HJ
authors.lastname: Han
authors.forename: Gye-Yeop
authors.initials: GY
authors.lastname: Kim
authors.forename: Soo Hyun
authors.initials: SH
authors.lastname: Park
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D019138:Antibodies, Blocking / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D003847:Deoxyglucose / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression; D005947:Glucose / Q000494:pharmacology*; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010857:Pigment Epithelium of Eye / Q000187:drug effects* / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D019138:Antibodies, Blocking; D000975:Antioxidants; D002867:Chromones; D003847:Deoxyglucose; D004791:Enzyme Inhibitors; D005947:Glucose; D051272:Glucose Transporter Type 1; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D000077191:Wortmannin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one