Effects of A2E-Induced Oxidative Stress on Retinal Epithelial Cells: New Insights on Differential Gene Response and Retinal Dystrophies

Abstract

Oxidative stress represents one of the principal inductors of lifestyle-related and genetic diseases. Among them, inherited retinal dystrophies, such as age-related macular degeneration and retinitis pigmentosa, are well known to be susceptible to oxidative stress. To better understand how high reactive oxygen species levels may be involved in retinal dystrophies onset and progression, we performed a whole RNA-Seq experiment. It consisted of a comparison of transcriptomes’ profiles among human retinal pigment epithelium cells exposed to the oxidant agent N-retinylidene-N-retinylethanolamine (A2E), considering two time points (3h and 6h) after the basal one. The treatment with A2E determined relevant differences in gene expression and splicing events, involving several new pathways probably related to retinal degeneration. We found 10 different clusters of pathways involving differentially expressed and differentially alternative spliced genes and highlighted the sub- pathways which could depict a more detailed scenario determined by the oxidative-stress-induced condition. In particular, regulation and/or alterations of angiogenesis, extracellular matrix integrity, isoprenoid-mediated reactions, physiological or pathological autophagy, cell-death induction and retinal cell rescue represented the most dysregulated pathways. Our results could represent an important step towards discovery of unclear molecular mechanisms linking oxidative stress and etiopathogenesis of retinal dystrophies.

The Relevance of Oxidative Stress in the Pathogenesis and Therapy of Retinal Dystrophies

“…The accumulation of lipofuscin and subsequent generation of ROS upon light damage is a well-known triggering factor of macular degeneration in AMD and Stargardt disease [65]. Recent transcriptomic studies on RPE cells treated with oxidizing agents produced in the visual cycle showed differential expression of genes involved in oxidative stress response, angiogenesis, apoptosis, autophagy, and extracellular matrix remodeling, but particularly alteration of miRNAs and target genes as well as of extensive alternative splicing events that could also relate to the regulation of specific survival pathways [66,67].…”

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.…”

Inhibition of MicroRNA 6937 Delays Photoreceptor and Vision Loss in a Mouse Model of Retinitis Pigmentosa

“…On the basis of the advances made by other research groups who have successfully used RNA interference technology for the in vitro and in vivo modulation of miRNA expression [ 40 , 41 ], and on previous observations regarding miRNA and mRNA aberrantly expressed, with relevance to retinitis pigmentosa [ 30 , 42 , 43 ], we worked under the hypothesis that the modulation of differentially expressed miRNAs in the retina of rd10 mice could slow down the progression of photoreceptor cell death.…”