title: Aldose reductase inhibition alleviates hyperglycemic effects on human retinal pigment epithelial cells.
abstract: Chronic hyperglycemia is an important risk factor involved in the onset and progression of diabetic retinopathy (DR). Among other effectors, aldose reductase (AR) has been linked to the pathogenesis of this degenerative disease. The purpose of this study was to investigate whether the novel AR inhibitor, beta-glucogallin (BGG), can offer protection against various hyperglycemia-induced abnormalities in human adult retinal pigment epithelial (ARPE-19) cells. AR is an enzyme that contributes to cellular stress by production of reactive oxygen species (ROS) under high glucose conditions. A marked decrease in cell viability (from 100% to 78%) following long-term exposure (4 days) of RPE cells to high glucose (HG) was largely prevented by siRNA-mediated knockdown of AR gene expression (from 79% to 97%) or inhibition using sorbinil (from 66% to 86%). In HG, BGG decreased sorbitol accumulation (44%), ROS production (27%) as well as ER stress (22%). Additionally, we demonstrated that BGG prevented loss of mitochondrial membrane potential (MMP) under HG exposure. We also showed that AR inhibitor pretreatment reduced retinal microglia-induced apoptosis in APRE-19 cells. These results suggest that BGG may be useful as a therapeutic agent against retinal degeneration in the diabetic eye by preventing RPE cell death.
authors.affiliation: Department of Ophthalmology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Kun-Che
authors.initials: KC
authors.lastname: Chang
authors.affiliation: Department of Ophthalmology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Anson
authors.initials: A
authors.lastname: Snow
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Daniel V
authors.initials: DV
authors.lastname: LaBarbera
authors.affiliation: Department of Ophthalmology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA. Electronic address: mark.petrash@ucdenver.edu.
authors.forename: J Mark
authors.initials: JM
authors.lastname: Petrash
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003930:Diabetic Retinopathy / Q000188:drug therapy / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006801:Humans; D047348:Hydrolyzable Tannins / Q000494:pharmacology; D006943:Hyperglycemia / Q000188:drug therapy* / Q000378:metabolism; D048289:Imidazolidines / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D017628:Microglia / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012168:Retinal Pigments / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D047348:Hydrolyzable Tannins; D048289:Imidazolidines; D017382:Reactive Oxygen Species; D012168:Retinal Pigments; C060474:glucogallin; D000449:Aldehyde Reductase; C026411:sorbinil; D005947:Glucose
keywords: Aldose reductase; ER stress; High glucose; Mitochondria; Retinal microglia; Retinal pigment epithelium