Abstract
The importance of extracellular vesicles (EVs) as signaling mediators has been emphasized for several pathways with only limited data regarding their role as protective messages during oxidative stress (OS). The ocular drainage system is unique by being continuously exposed to OS and having a one-way flow of the aqueous humor carrying EVs taking role in glaucoma disease. Here, we aimed to examine the ability of EVs derived from the non-pigmented ciliary epithelium (NPCE)—the aqueous humor producing cells exposed to OS—to deliver protecting messages to the trabecular meshwork (TM)—the aqueous humor draining cells—a process with significance to the pathophysiology of glaucoma disease. EVs extracted from media of NPCE cells exposed to non-lethal OS and their unstressed control were incubated with TM cells. The effects of EVs derived from oxidative stressed cells on the activation of the nuclear factor erythroid 2-related factor 2-Kelch-like ECH-associated protein 1 (Nrf2-Keap1), a major OS pathway, and of the Wnt pathway, known for its role in primary open-angle glaucoma, were evaluated. EVs derived from oxidized NPCE cells significantly protected TM cells from direct OS. The TM cells uptake of EVs from oxidized NPCE and their cytosolic Nrf2 levels were significantly higher at 8 h post-exposure. EVs derived from oxidized NPCE cells significantly attenuated Wnt protein expression in TM cells and activated major antioxidant genes as measured by qRT-PCR. TM cells exposed to EVs derived from oxidized NPCE cells exhibited significantly lower OS and higher super oxide dismutase and catalase activity. Finally, we were able to show that carbonylated proteins and products of oxidized protein are presented in significantly higher levels in EVs derived from oxidized NPCE cells, supporting their suggested role in the signaling process. We hypothesize that these findings may have implications beyond understanding the pathophysiology of glaucoma disease and that transmitting signals that activate the antioxidant system in target cells represent a broad response common to many tissues communication.
Highlights
Communication mediated by extracellular vesicles (EVs) has been shown to be part of tissue and organ general homeostasis and plays a significant role during pathologies
We investigated whether exposure of trabecular meshwork (TM) cells to EVs produced by non-pigmented ciliary epithelium (NPCE) cells under Oxidative stress (OS) conditions can result in TM biology changes inducing cell-protective mechanisms
The results show that expression levels of p-GSK3β and β-catenin were reduced in the TM cells co-cultured either with EVs-OS or EVs-N than untreated TM and OS TM at 8 h
Summary
Communication mediated by extracellular vesicles (EVs) has been shown to be part of tissue and organ general homeostasis and plays a significant role during pathologies. Oxidative stress (OS) due to imbalance between cell oxidant exposure and cell antioxidant capacity plays a pivotal role in determining cell fate. It is accepted among the scientific community that redox balance is one of the tightly controlled homeostasis parameters resembling physiological pH levels control. Local changes in OS are responded by corresponding changes in antioxidant capacity of the cells and tissues. The cellular defense mechanisms against OS include low molecular weight antioxidants and antioxidant enzymes. One of the key redox regulating systems allowing cells to respond to OS is the Nrf2-Keap pathway. Nrf is an intracellular transcription factor that regulates the expression of genes encoding antioxidant enzymes, low molecular weight antioxidants, anti-apoptotic proteins, and drug transporters. High amount of ROS activates tyrosine kinases to dissociate Nrf2-Keap complex, Nrf translocate to the nucleus where a coordinated activation of cytoprotective gene expression takes place [1]
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