Transcriptome Analyses of lncRNAs in A2E-Stressed Retinal Epithelial Cells Unveil Advanced Links between Metabolic Impairments Related to Oxidative Stress and Retinitis Pigmentosa

Abstract

Long non-coding RNAs (lncRNAs) are untranslated transcripts which regulate many biological processes. Changes in lncRNA expression pattern are well-known related to various human disorders, such as ocular diseases. Among them, retinitis pigmentosa, one of the most heterogeneous inherited disorder, is strictly related to oxidative stress. However, little is known about regulative aspects able to link oxidative stress to etiopathogenesis of retinitis. Thus, we realized a total RNA-Seq experiment, analyzing human retinal pigment epithelium cells treated by the oxidant agent N-retinylidene-N-retinylethanolamine (A2E), considering three independent experimental groups (untreated control cells, cells treated for 3 h and cells treated for 6 h). Differentially expressed lncRNAs were filtered out, explored with specific tools and databases, and finally subjected to pathway analysis. We detected 3,3'-overlapping ncRNAs, 107 antisense, 24 sense-intronic, four sense-overlapping and 227 lincRNAs very differentially expressed throughout all considered time points. Analyzed lncRNAs could be involved in several biochemical pathways related to compromised response to oxidative stress, carbohydrate and lipid metabolism impairment, melanin biosynthetic process alteration, deficiency in cellular response to amino acid starvation, unbalanced regulation of cofactor metabolic process, all leading to retinal cell death. The explored lncRNAs could play a relevant role in retinitis pigmentosa etiopathogenesis, and seem to be the ideal candidate for novel molecular markers and therapeutic strategies.

Correlation between Visual Acuity and Optical Coherence Tomography Angiography Parameters in Unilateral Idiopathic Epiretinal Membrane

“…Nishida et al found that subfoveal choroidal thickness is the only significant predictor of visual acuity in highly myopic eyes. They suggested that the thin choroid of highly myopic eyes may deliver decreased amounts of nutrients and oxygen to the outer retina, which may consequently affect the function and structures of the photoreceptors [ 30 , 31 , 32 , 33 ]. In our study, we extended the scope and found that macular flow density of choriocapillaris was the only significant factor correlated with visual acuity in iERM eyes.…”

Antioxidant and Biological Properties of Mesenchymal Cells Used for Therapy in Retinitis Pigmentosa

“…In recent years, it has been demonstrated that the oxidative damage can also interfere with particular RNA molecules called long non-coding RNAs [ 80 , 81 ]. These are involved in several critical biochemical pathways, such as chromosome conformation modeling, genomic imprinting modulation, allosteric control of enzymatic activity, as well as cell state coordination, differentiation, and development.…”

“…These are involved in several critical biochemical pathways, such as chromosome conformation modeling, genomic imprinting modulation, allosteric control of enzymatic activity, as well as cell state coordination, differentiation, and development. Dysregulation or mutation of non-coding genes has been associated with various human diseases, including RP [ 80 , 81 ].…”

Possible A2E Mutagenic Effects on RPE Mitochondrial DNA from Innovative RNA-Seq Bioinformatics Pipeline

“…Drusen consist of mixtures of high photo-sensitive lipofuscin, involved in the first photo-sensitive reactions, caused by the generation of singlet oxygen and superoxide anion. A2E is one of the most abundant components of drusen, and a direct transmittal of light to the retina by drusen determines its cleavage at the pyridinium ring, inducing oxidative stress [ 17 , 18 , 19 ]. Thus, the main purpose of our study was the identification of mtDNA variants that might be induced by intense oxidative stress, together with their possible related molecular pathways most likely linked to retinal degeneration onset and/or progression.…”