Differential Modulation of MAPKs in Relation to Increased Intraocular Pressure in the Aqueous Humor of Rat Eye Injected with Hyaluronic Acid

Shmulevich, A.; Beit‐Yannai, Elie

doi:10.1080/02713680902916090

Cited by 10 publications

(6 citation statements)

References 43 publications

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“…AqH is the optically clear fluid supplying the avascular tissues with oxygen, nutrients, antioxidants as well as carrying out waist products. AqH was reported to mediate mitogen-activated protein kinase signals, phosphatase and matrix metalloproteinases activation in TM cells [ 12 , 13 ]. AqH is produced by the non-pigmented ciliary epithelium (NPCE) of the ciliary processes and it has been hypothesized to convey signaling message between the ciliary epithelium tissue and the TM [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Extracellular Vesicles Mediate Anti-Oxidative Response—In Vitro Study in the Ocular Drainage System

Lerner

Chen

Schreiber‐Avissar

et al. 2020

IJMS

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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.

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Section: Introductionmentioning

confidence: 99%

Extracellular Vesicles Mediate Anti-Oxidative Response—In Vitro Study in the Ocular Drainage System

Lerner

Chen

Schreiber‐Avissar

et al. 2020

IJMS

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“…Active proteins [ 4 ] have been detected in the AH, supporting the idea of tissue communication within the drainage system. Among AH proteins, some were uniquely identified in the AH, while many others, such as cytokines [ 5 ], kinases [ 6 ], phosphatases [ 7 ], growth factors [ 8 ], are general participants of cellular communication. Further support for communication between the ocular drainage systems came from cell culture experiments where co-cultured non-pigmented ciliary epithelium (NPCE) and TM cells induced significant increases in the activity of some phosphatases and MMPs (matrix metalloproteinases ), MMP-2 and MMP-9,) in TM cells [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Extracellular vesicles mediate signaling between the aqueous humor producing and draining cells in the ocular system

2017

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PurposeCanonical Wnt signaling is associated with glaucoma pathogenesis and intraocular pressure (IOP) regulation. Our goal was to gain insight into the influence of non-pigmented ciliary epithelium (NPCE)-derived exosomes on Wnt signaling by trabecular meshwork (TM) cells. The potential impact of exosomes on Wnt signaling in the ocular drainage system remains poorly understood.MethodsExosomes isolated from media collected from cultured NPCE cells by differential ultracentrifugation were characterized by dynamic light scattering (DLS), tunable resistive pulse sensing (TRPS), and nanoparticle tracking analysis (NTA), sucrose density gradient migration and transmission electron microscopy (TEM). The cellular target specificity of the NPCE-derived exosomes was investigated by confocal microscopy-based monitoring of the uptake of DiD-labeled exosomes over time, as compared to uptake by various cell lines. Changes in Wnt protein levels in TM cells induced by NPCE exosomes were evaluated by Western blot.ResultsExosomes derived from NPCE cells were purified and detected as small rounded 50–140 nm membrane vesicles, as defined by DLS, NTA, TRPS and TEM. Western blot analysis indicated that the nanovesicles were positive for classic exosome markers, including Tsg101 and Alix. Isolated nanoparticles were found in sucrose density fractions typical of exosomes (1.118–1.188 g/mL sucrose). Using confocal microscopy, we demonstrated time-dependent specific accumulation of the NPCE-derived exosomes in NTM cells. Other cell lines investigated hardly revealed any exosome uptake. We further showed that exosomes induced changes in Wnt signaling protein expression in the TM cells. Western blot analysis further revealed decreased phosphorylation of GKS3β and reduced β-catenin levels. Finally, we found that treatment of NTM cells with exosomes resulted in a greater than 2-fold decrease in the level of β-catenin in the cytosolic fraction. In contrast, no remarkable difference in the amount of β-catenin in the nuclear fraction was noted, relative to the control.ConclusionsThe data suggest that NPCE cells release exosome-like vesicles and that these nanoparticles affect canonical Wnt signaling in TM cells. These findings may have therapeutic relevance since canonical Wnt pathway is involved in intra-ocular pressure regulation. Further understanding of NPCE-derived exosome-responsive signaling pathways may reveal new targets for pharmacological intervention within the drainage system as a target for glaucoma therapy.

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“…30 In our previous studies we detected MAPK proteins in rat AH and showed that their expression levels were affected by the degree of IOP. 22 Although the sources for MAPK remained obscure, we speculated that phosphatases-the counterbalancing enzymes of these kinases-might be present in AH as well. Results of the present study confirmed this hypothesis and may contribute to the hypothesis of Coca-Prados and Escribano 37 that paracrine and autocrine effects within the anterior chamber might be mediated by the AH.…”

Section: Discussionmentioning

confidence: 99%

“…20 We previously suggested that serine/threonine kinases take part in AH outflow control 21 and showed that changes in MAPK protein expression and activation occur within the AH of a rat model of induced elevated IOP. 22 It was suggested that there is a close and direct signaling effect between redox state and kinase/phosphatase activity. 23 Dephosphorylation of specific phosphorylated sites can inhibit kinase activity.…”

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confidence: 99%

Human Aqueous Humor Phosphatase Activity in Cataract and Glaucoma

Latarya

Mansour

Epstein

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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Differential Modulation of MAPKs in Relation to Increased Intraocular Pressure in the Aqueous Humor of Rat Eye Injected with Hyaluronic Acid

Abstract: We suggest that these signaling molecules might be a new target for intervention, opening new possibilities for intraocular pressure management.

Cited by 10 publications

References 43 publications

Extracellular Vesicles Mediate Anti-Oxidative Response—In Vitro Study in the Ocular Drainage System

Extracellular Vesicles Mediate Anti-Oxidative Response—In Vitro Study in the Ocular Drainage System

Extracellular vesicles mediate signaling between the aqueous humor producing and draining cells in the ocular system

Human Aqueous Humor Phosphatase Activity in Cataract and Glaucoma

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