Abstract
In glaucoma, retinal ganglion cells are damaged, leading to the progressive constriction of the visual field. We have previously shown that the valosin-containing protein (VCP) modulators, Kyoto University Substance (KUS)121 and KUS187, prevent the death of retinal ganglion cells in animal models of glaucoma, including the one generated by N-methyl-D-aspartate (NMDA)-induced neurotoxicity. KUSs appeared to avert endoplasmic reticulum (ER) stress by maintaining ATP levels, resulting in the protection of ganglion cells from cell death. To further elucidate the protective mechanisms of KUSs, we examined gene expression profiles in affected ganglion cells. We first injected KUS-treated mice with NMDA and then isolated the affected retinal ganglion cells using fluorescence-activated cell sorting. Gene expression in the cells was quantified using a next-generation sequencer. Resultantly, we found that KUS121 upregulated several genes involved in energy metabolism. In addition, we observed the upregulation of Zfp667, which has been reported to suppress apoptosis-related genes and prevent cell death. These results further support the suitability of KUS121 as a therapeutic drug in protecting retinal ganglion cells in ophthalmic disorders, such as glaucoma.
Highlights
In glaucoma, retinal ganglion cells are damaged, leading to the progressive constriction of the visual field
To decide the timing for evaluation of gene expression after intravitreous NMDA injection, the mRNA levels of 18 genes, of which some were reported to be upregulated after NMDA injection and some could be influenced by administration of Kyoto University Substance (KUS), were analysed using quantitative reverse transcription polymerase chain reaction
We successfully isolated retinal ganglion cells to a high level of purity using fluorescence-activated cell sorting (FACS) and found that KUSs affect the expression of a wide variety of genes
Summary
Retinal ganglion cells are damaged, leading to the progressive constriction of the visual field. We have previously shown that the valosin-containing protein (VCP) modulators, Kyoto University Substance (KUS)[121] and KUS187, prevent the death of retinal ganglion cells in animal models of glaucoma, including the one generated by N-methyl-D-aspartate (NMDA)-induced neurotoxicity. We observed the upregulation of Zfp[667], which has been reported to suppress apoptosis-related genes and prevent cell death These results further support the suitability of KUS121 as a therapeutic drug in protecting retinal ganglion cells in ophthalmic disorders, such as glaucoma. In addition to the suppression of the decrease of ATP levels, we aimed to clarify the potential involvement of cellular genes by the KUS treatment Towards this end, isolation and collection of retinal ganglion cells is needed because they consist of only a small proportion of retinal cells[20]. We used next-generation sequencing technologies[33] to compare gene expression profiles between with and without KUS treatments
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