Abstract
Glaucoma, a group of eye diseases, causes gradual loss of retinal ganglion cells (RGCs) and ultimately results in irreversible blindness. Studies of the underlying mechanisms of glaucoma and clinical trial are far from satisfactory. Results from a genome-wide association study have suggested that the CAV1/CAV2 locus is associated with glaucoma, but this association and its potential underlying mechanisms need to be confirmed and further explored. Here, we studied the function of caveolin-1 (Cav1) in an acute ocular hypertension glaucoma model. Cav1 deficiency caused an aggregated lesion in the retina. In addition, treatment with cavtratin, a membrane permeable Cav1 scaffolding domain peptide, enhanced RGC survival. After cavtratin treatment, microglial numbers decreased significantly, and the majority of them migrated from the inner retinal layer to the outer retinal layers. Furthermore, cavtratin promoted a change in the microglia phenotype from the neurotoxic pro-inflammatory M1 to the neuroprotective anti-inflammatory M2. In a molecular mechanism experiment, we found that cavtratin activated the phosphorylation of both AKT and PTEN in cultured N9 cells. Our data highlights the neuroprotective effect of Cav1 on acute ocular hypertension and suggests that Cav1 may serve as a novel therapeutic target for the treatment of glaucoma. We further propose that cavtratin is a therapeutic candidate for glaucoma clinical trials.
Highlights
Glaucoma, a group of eye diseases, causes gradual loss of retinal ganglion cells (RGCs) and results in irreversible blindness
To explore whether Cav[1] was involved in the pathogenesis of acute ocular hypertension injury, we examined its expression in the retina of an animal model
The immunostaining results revealed that the ratio of CD16/32+ M1 cells to the total Iba1+ cells decreased by approximately 4 times in the cavtratin group (Figs 6C and 6D), while the ratio of CD206+ cells to the total Iba1+ cells increased by approximately 3 times (Fig. 6E,F). These results indicate that cavtratin modulates change in the microglial phenotype from the neurotoxic pro-inflammatory M1 phenotype to the neuroprotective anti-inflammatory M2 phenotype, which reveals the neuroprotective mechanism of cavtratin in acute ocular hypertension injury at the cellular level
Summary
A group of eye diseases, causes gradual loss of retinal ganglion cells (RGCs) and results in irreversible blindness. Results from a genome-wide association study have suggested that the CAV1/CAV2 locus is associated with glaucoma, but this association and its potential underlying mechanisms need to be confirmed and further explored. We studied the function of caveolin-1 (Cav1) in an acute ocular hypertension glaucoma model. Treatment with cavtratin, a membrane permeable Cav[1] scaffolding domain peptide, enhanced RGC survival. Glaucoma is a group of eye diseases characterized by optic neuropathy and progressive degeneration of RGCs that results in irreversible blindness[1]. As the major structure protein of caveolae, Cav[1] dysfunction has been linked to a wide range of diseases, such as lipodystrophy, muscular dystrophies, cardiac disease, infection, Alzheimer’s disease, Parkinson’s disease and cancer[15,16,17]. Cavtratin works as either an analog or a dominant negative of Cav[1], depending on the binding sites of the corresponding interacting proteins and their functions[23, 24]
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