Effect of NK-5962 on Gene Expression Profiling of Retina in a Rat Model of Retinitis Pigmentosa.

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.

• Authors: Shihui Liu, Mary Miyaji, Osamu Hosoya, Toshihiko Matsuo
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 24 (Dec 10 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 34948073 (Publication Type: Journal Article)

Chemical References

• 2-(2-(4-(dibutylamino)phenyl)ethenyl)-3-carboxymethylbenzothiazolium
• Aniline Compounds
• Eye Proteins
• Nerve Growth Factors
• Serpins
• Thiazoles
• pigment epithelium-derived factor

Topics

• Aniline Compounds (administration & dosage, therapeutic use)
• Animals
• Apoptosis
• Computational Biology
• Disease Models, Animal
• Eye Proteins (genetics, physiology)
• Gene Expression Regulation
• Gene Ontology
• Intravitreal Injections
• Male
• Nerve Growth Factors (genetics, physiology)
• RNA-Seq
• Rats
• Retina (metabolism, physiopathology)
• Retinitis Pigmentosa (drug therapy, genetics, metabolism, physiopathology)
• Serpins (genetics, physiology)
• Thiazoles (administration & dosage, therapeutic use)
• Visual Prosthesis