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Abstract
Purpose: NK-5962 is a key component of photoelectric dye-coupled polyethylene film, designated Okayama University type-retinal prosthesis (OUReP™). Previously, we found that NK-5962 solution could reduce the number of apoptotic photoreceptors in the eyes of the Royal College of Surgeons (RCS) rats by intravitreal injection under a 12 h light/dark cycle. This study aimed to explore possible molecular mechanisms underlying the anti-apoptotic effect of NK-5962 in the retina of RCS rats. Methods: RCS rats received intravitreal injections of NK-5962 solution in the left eye at the age of 3 and 4 weeks, before the age of 5 weeks when the speed in the apoptotic degeneration of photoreceptors reaches its peak. The vehicle-treated right eyes served as controls. All rats were housed under a 12 h light/dark cycle, and the retinas were dissected out at the age of 5 weeks for RNA sequence (RNA-seq) analysis. For the functional annotation of differentially expressed genes (DEGs), the Metascape and DAVID databases were used. Results: In total, 55 up-regulated DEGs, and one down-regulated gene (LYVE1) were found to be common among samples treated with NK-5962. These DEGs were analyzed using Gene Ontology (GO) term enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome pathway analyses. We focused on the up-regulated DEGs that were enriched in extracellular matrix organization, extracellular exosome, and PI3K–Akt signaling pathways. These terms and pathways may relate to mechanisms to protect photoreceptor cells. Moreover, our analyses suggest that SERPINF1, which encodes pigment epithelium-derived factor (PEDF), is one of the key regulatory genes involved in the anti-apoptotic effect of NK-5962 in RCS rat retinas. Conclusions: Our findings suggest that photoelectric dye NK-5962 may delay apoptotic death of photoreceptor cells in RCS rats by up-regulating genes related to extracellular matrix organization, extracellular exosome, and PI3K–Akt signaling pathways. Overall, our RNA-seq and bioinformatics analyses provide insights in the transcriptome responses in the dystrophic RCS rat retinas that were induced by NK-5962 intravitreal injection and offer potential target genes for developing new therapeutic strategies for patients with retinitis pigmentosa.
Highlights
Retinitis pigmentosa (RP) is a hereditary disease that causes blindness due to the loss of retinal photoreceptor cells
We found that the NK-5962 molecule itself protected both neural retinal cells and retinal pigment epithelial (RPE) cells from apoptosis through the primary mixed culture of retinal cells, NK-5962 coupled film transplanted into the eyes of Royal College of Surgeons (RCS) rats, and intravitreal injection of NK-5962 solution in RCS rats [22,23,24]
The FGFR2 gene is a factor that mediates the rescue of photoreceptors in the rat and has an effect on anti-apoptotic and neurite repair [93,94]. These results indicate that the delivery of NK-5962 maybe protect photoreceptors from apoptosis in RCS rat through up-regulated FGFR2 gene by activating the PI3K–Akt signaling pathway
Summary
Retinitis pigmentosa (RP) is a hereditary disease that causes blindness due to the loss of retinal photoreceptor cells. Patients with RP experience slowly progressive loss in the peripheral visual field, leading to blindness in later decades [1]. In the RCS rat, a 409 bp deletion in the receptor tyrosine kinase MERTK gene mutation leads to reduced phagocytic function of the retinal pigment epithelial (RPE) cells and causes accumulation of photoreceptor outer segment debris in the subretinal space. Later, this debris blocks efficient oxygen and nutrient transport to photoreceptor cells and leads to progressive photoreceptor degeneration and subsequent vison decline [14,15,16]. Apoptosis of photoreceptors reaches its peak on P32, and it gradually decreases [17]
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