The Intertwined Roles of Oxidative Stress and Endoplasmic Reticulum Stress in Glaucoma

Abstract

Glaucoma is the leading cause of irreversible blindness worldwide, and the burden of the disease continues to grow as the global population ages. Currently, the only treatment option is to lower intraocular pressure. A better understanding of glaucoma pathogenesis will help us to develop novel therapeutic options. Oxidative stress has been implicated in the pathogenesis of many diseases. Oxidative stress occurs when there is an imbalance in redox homeostasis, with reactive oxygen species producing processes overcoming anti-oxidant defensive processes. Oxidative stress works in a synergistic fashion with endoplasmic reticulum stress, to drive glaucomatous damage to trabecular meshwork, retinal ganglion cells and the optic nerve head. We discuss the oxidative stress and endoplasmic reticulum stress pathways and their connections including their key intermediary, calcium. We highlight therapeutic options aimed at disrupting these pathways and discuss their potential role in glaucoma treatment.

Anti-apoptotic and autophagic effect: Using conditioned medium from human bone marrow mesenchymal stem cells to treat human trabecular meshwork cells

“…The results showed that 1X and 5X CM from MSCs decreases the mitochondrial ROS production after oxidative damage and decreases apoptosis-related DNA fragmentation. As many studies have demonstrated a major role of oxidative stress in the pathogenesis of glaucoma [ [26] , [27] , [28] ], we used an oxidatively damaged TM cell model to simulate glaucomatous TM cells, which are characterized by increased expression of oxidative markers and diminished antioxidant potential [ [29] , [30] , [31] ].…”

Genome-Wide RNA Sequencing of Human Trabecular Meshwork Cells Treated with TGF-β1: Relevance to Pseudoexfoliation Glaucoma

“…The inhibition of YAP with verteporfin in lamina cribrosa cells showed therapeutic benefits [ 105 ]. ER stress and the unfolded protein response (UPR) have also gained interest in glaucoma and ophthalmology as therapeutic targets [ 106 , 107 , 108 ]. There are a number of potentially druggable stress pathways [ 107 ] and genetic manipulation or pharmacological inhibition of the ATF4–CHOP–GADD34 pathway has shown therapeutic benefit in the trabecular meshwork in murine and human glaucoma [ 108 , 109 ].This cellular model of pseudoexfoliation glaucoma cannot capture all features of this complex disease, but can provide some insight into disease pathogenesis and support the development of novel therapeutic interventions.…”

The Role of Oxidative Stress in the Aging Eye

“…This age-dependent increase in ROS is also accompanied by diminished antioxidant levels, including superoxide dismutase, Vitamin C, and Vitamin E [ 99 ]. Oxidative stress plays a significant role in several of the most common age-linked eye diseases ( Figure 4 ) [ 100 ].…”