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Aldose reductase inhibition alleviates hyperglycemic effects on human retinal pigment epithelial cells
Kun-Che Chang1, Anson Snow2, Daniel V LaBarbera3
1Department 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.
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.
Insights
Beta-glucogallin (BGG), a novel aldose reductase (AR) inhibitor, protects retinal pigment epithelial cells from high glucose damage. BGG reduces oxidative stress and cell death, offering potential therapeutic benefits for diabetic retinopathy.
Area of Science:
- Ophthalmology
- Cell Biology
- Biochemistry
Background:
- Diabetic retinopathy (DR) is a degenerative eye disease linked to chronic hyperglycemia.
- Aldose reductase (AR) plays a role in DR pathogenesis by increasing oxidative stress under high glucose conditions.
Purpose of the Study:
- To evaluate the protective effects of beta-glucogallin (BGG), a novel AR inhibitor, against hyperglycemia-induced damage in human adult retinal pigment epithelial (ARPE-19) cells.
Main Methods:
- ARPE-19 cells were exposed to high glucose (HG) conditions.
- Effects of BGG, AR gene knockdown (siRNA), and sorbinil on cell viability, sorbitol accumulation, reactive oxygen species (ROS) production, ER stress, and mitochondrial membrane potential (MMP) were assessed.
- Apoptosis induced by retinal microglia was also evaluated.
Main Results:
- High glucose significantly reduced ARPE-19 cell viability, which was restored by AR inhibition (BGG or sorbinil) or AR gene knockdown.
- BGG treatment decreased sorbitol accumulation, ROS production, and ER stress in HG-exposed cells.
- BGG also prevented loss of MMP and reduced microglia-induced apoptosis in ARPE-19 cells.
Conclusions:
- Beta-glucogallin demonstrates significant protective effects against hyperglycemia-induced cellular abnormalities in retinal pigment epithelial cells.
- BGG's ability to mitigate oxidative stress, ER stress, and apoptosis suggests its potential as a therapeutic agent for preventing RPE cell death and treating diabetic retinopathy.
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