The study of aldose reductase and eye disease

Abstract

Aldose reductase (AR) is an NADPH-dependent aldo-keto reductase that has been shown to be involved in the pathogenesis of several blinding diseases such as uveitis, diabetic retinopathy (DR) and cataract. However, possible mechanisms linking the action of AR to these diseases are not well understood. As DR and cataract are among the leading causes of blindness in the world, there is an urgent need to explore therapeutic strategies for prevention or delay in the onset and development of DR and cataracts. The following studies were carried out to better understand the potential mechanisms linking AR to inflammatory changes associated with uveitis and DR as well as growth factor-signaling cascades associated with cataractogenesis. We also tested whether inhibition of AR has potential as a therapeutic strategy in these blinding diseases. In our endotoxin-induced uveitis (EIU) study, I found that the natural compound, beta-glucogallin (BGG) has inhibitory activity against AR with very low cytotoxicity. Intraperitoneal injection of BGG is able to prevent endotoxin-induced immune cells infiltration into the eye. Retinal microglia (RMG) are one of the major cell types in charge of immune surveillance in the retina. I observed that pharmacological inhibition or genetic ablation of AR attenuates LPS-induced inflammatory responses in RMG of the EIU mouse model. In our DR study, I observed that treatment of a retinal pigment epithelium (RPE) immortalized cell line with an AR inhibitor alleviated hyperglycemia-induced cell death, osmotic stress, ER stress and mitochondrial dysfunction. Secretion of vascular endothelial growth factor (VEGF) in retina causes neovascularization, which can lead to retinal edema. I also observed that downregulation of AR is able to reduce hypoxia-induced VEGF secretion from RMG and prevent advanced glycation endproducts (AGEs)-induced inflammatory responses in RMG. PCO is a frequent complication of cataract surgery, and is associated with abnormal cell growth, migration and epithelial-to-mesenchymal transition (EMT)-associated differentiation. Transforming growth factor beta (TGF-β) is thought to induce the EMT changes following cataract surgery, acting through the SMAD signaling pathway. In my PCO study, I observed that AR inhibitor pretreatment of lens epithelial cells attenuated TGF-β-induced cell migration, SMADs phosphorylation, matrix metalloproteinase activation and EMT marker expression. I further observed that AR enzymatic activity is not required for its interactions with SMADs. In addition, I determined that the AR inhibitor Sorbinil disrupts the AR-SMAD interaction, which reduces the effect of SMADs signaling to induce expression of EMT-associated genes. In summary, I observed that AR is involved in RMG-activated inflammatory responses in retina and TGF-β-induced EMT in lens epithelial cells, which provide a therapeutic target for retinal degeneration, neovascularization and PCO progression.