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Role of oxidative stress in Retinitis pigmentosa: new involved pathways by an RNA-Seq analysis.

ABSTRACT: Retinitis pigmentosa (RP) is a very heterogeneous inherited ocular disorder group characterized by progressive retinal disruption. Retinal pigment epithelium (RPE) degeneration, due to oxidative stress which arrests the metabolic support to photoreceptors, represents one of the principal causes of RP. Here, the role of oxidative stress in RP onset and progression was analyzed by a comparative whole transcriptome analysis of human RPE cells, treated with 100 µg/ml of oxLDL and untreated, at different time points. Experiment was thrice repeated and performed on Ion ProtonTM sequencing system. Data analysis, including low quality reads trimming and gene expression quantification, was realized by CLC Genomics Workbench software. The whole analysis highlighted 14 clustered "macro-pathways" and many sub-pathways, classified by selection of 5271 genes showing the highest alteration of expression. Among them, 23 genes were already known to be RP causative ones (15 over-expressed and 8 down-expressed), and their enrichment and intersection analyses highlighted new 77 candidate related genes (49 over-expressed and 28 down-expressed). A final filtering analysis then highlighted 29 proposed candidate genes. This data suggests that many new genes, not yet associated with RP, could influence its etiopathogenesis.

SUBMITTER: Donato L

PROVIDER: S-EPMC6343708 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Role of oxidative stress in Retinitis pigmentosa: new involved pathways by an RNA-Seq analysis.

Donato Luigi L Scimone Concetta C Nicocia Giacomo G D'Angelo Rosalia R Sidoti Antonina A

Cell cycle (Georgetown, Tex.) 20181228 1

Retinitis pigmentosa (RP) is a very heterogeneous inherited ocular disorder group characterized by progressive retinal disruption. Retinal pigment epithelium (RPE) degeneration, due to oxidative stress which arrests the metabolic support to photoreceptors, represents one of the principal causes of RP. Here, the role of oxidative stress in RP onset and progression was analyzed by a comparative whole transcriptome analysis of human RPE cells, treated with 100 µg/ml of oxLDL and untreated, at diffe ...[more]

PMID: 30569795

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Project description:Hereditary retinal degenerations like retinitis pigmentosa (RP) are among the leading causes of blindness in younger patients. To enable in vivo investigation of cellular and molecular mechanisms responsible for photoreceptor cell death and to allow testing of therapeutic strategies that could prevent retinal degeneration, animal models have been created. In this study, we deeply characterized the transcriptional profile of mice carrying the transgene rhodopsin V20G/P23H/P27L (VPP), which is a model for autosomal dominant RP. We examined the degree of photoreceptor degeneration and studied the impact of the VPP transgene-induced retinal degeneration on the transcriptome level of the retina using next generation RNA sequencing (RNASeq) analyses followed by weighted correlation network analysis (WGCNA). We furthermore identified cellular subpopulations responsible for some of the observed dysregulations using in situ hybridizations, immunofluorescence staining, and 3D reconstruction. Using RNASeq analysis, we identified 9256 dysregulated genes and six significantly associated gene modules in the subsequently performed WGCNA. Gene ontology enrichment showed, among others, dysregulation of genes involved in TGF-β regulated extracellular matrix organization, the (ocular) immune system/response, and cellular homeostasis. Moreover, heatmaps confirmed clustering of significantly dysregulated genes coding for components of the TGF-β, G-protein activated, and VEGF signaling pathway. 3D reconstructions of immunostained/in situ hybridized sections revealed retinal neurons and Müller cells as the major cellular population expressing representative components of these signaling pathways. The predominant effect of VPP-induced photoreceptor degeneration pointed towards induction of neuroinflammation and the upregulation of neuroprotective pathways like TGF-β, G-protein activated, and VEGF signaling. Thus, modulation of these processes and signaling pathways might represent new therapeutic options to delay the degeneration of photoreceptors in diseases like RP.

Dataset Information

Role of oxidative stress in Retinitis pigmentosa: new involved pathways by an RNA-Seq analysis.

Publications

Role of oxidative stress in Retinitis pigmentosa: new involved pathways by an RNA-Seq analysis.

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