Reduced inspired oxygen decreases retinal superoxide radicals and promotes cone function and survival in a model of retinitis pigmentosa.
Ontology highlight
ABSTRACT:
SUBMITTER: Kanan Y
PROVIDER: S-EPMC10000309 | biostudies-literature | 2023 Mar
REPOSITORIES: biostudies-literature
Publications
Reduced inspired oxygen decreases retinal superoxide radicals and promotes cone function and survival in a model of retinitis pigmentosa.
Kanan Yogita Y Hackett Sean F SF Hsueh Henry T HT Khan Mahmood M Ensign Laura M LM Campochiaro Peter A PA
Free radical biology & medicine 20230201
Retinitis pigmentosa (RP) is caused by many different mutations that promote the degeneration of rod photoreceptors and have no direct effect on cones. After the majority of rods have died cone photoreceptors begin to slowly degenerate. Oxidative damage contributes to cone cell death and it has been hypothesized that tissue hyperoxia due to reduced oxygen consumption from the loss of rods is what initiates oxidative stress. Herein, we demonstrate in animal models of RP that reduction of retinal ...[more]
Similar Datasets
Project description:PurposeTo measure the retinal oxygen metabolic function with retinal oximetry (RO) in patients with choroideremia (CHM) and compare these findings with retinitis pigmentosa (RP) patients and controls.MethodsProspective observational study including 18 eyes of 9 molecularly confirmed CHM patients (9♂; 40.2 ± 21.2 years (mean ± SD), 77 eyes from 39 patients with RP (15♀ 24♂; 45.6 ± 14.7 years) and 100 eyes from 53 controls (31♀ 22♂; 40.2 ± 13.4 years). Main outcome parameters were the mean arterial (A-SO2; %), venular (V-SO2; %) oxygen saturation, and their difference (A-V SO2; %) recorded with the oxygen saturation tool of the Retinal Vessel Analyzer (IMEDOS Systems UG, Germany). Statistical analyses were performed with linear mixed-effects models.ResultsEyes suffering from CHM differed significantly from both RP and control eyes, when the retinal oxygen metabolic parameters were taken into account. While RP showed significantly higher A-SO2 and V-SO2 values when compared to controls, CHM showed opposite findings with significantly lower values when compared to both RP and controls (P < 0.001). The A-V SO2, which represents the retinal oxygen metabolic consumption, showed significantly lower values in CHM compared to controls.ConclusionThe retina in CHM is a relatively hypoxic environment. The decrease in oxygen levels may be due to the profound choroidal degeneration, leading to decreased oxygen flux to the retina. RO measurements may help understand the pathogenesis of CHM and RP. These findings may provide useful details to inform the planning of clinical trials of emerging therapies for CHM.Key messagesWhat was known before? Retinal oxygen metabolic function measured with retinal oximetry (RO) shows significant alterations in patients with retinitis pigmentosa.What this study addsRO function in choroideremia is significantly altered when compared to controls. Furthermore, RO in choroideremia shows opposing findings within different oxygen metabolic parameters to those that were so far known for retinitis pigmentosa. By providing insights into the retinal oxygen metabolic mechanisms, RO can help understand the underlying pathophysiology in choroideremia.
| S-EPMC11868133 | biostudies-literature
Project description:Retinal dehydrogenase 12 (RDH12) is a photoreceptor NADPH-dependent retinal reductase enzyme, which converts all-trans-retinal to all-trans-retinol. In rare cases, heterozygous variants in RDH12 are associated with a mild, late-onset autosomal dominant (AD) retinitis pigmentosa (RP). There are no dominant RDH12 animal models, hence, we generated retinal organoids from human induced pluripotent stem cells (hiPSC) derived from dermal fibroblasts from a RDH12-AD patient with the heterozygous pathogenic variant c.759del p.(Phe254Leufs*24) and an unrelated unaffected individual (WT). Retinal organoids were characterised at different stages of differentiation; at 18-weeks there were no differences in rod and cone photoreceptors with correct localisation of RDH12 in the photoreceptor inner segments in both WT and RDH12-AD. Transmission electron microscopy on week 37 retinal organoids showed a normal outer limiting membrane and mitochondria, but photoreceptors were 1.8 times less abundant and shorter in RDH12-AD mutant compared to WT. Transcriptomic analyses on week 44 retinal organoids revealed visual cone function, retinol biosynthesis and the vitamin A pathway are highly affected in RDH12-AD retinal organoids. Our study is the first to describe a human RDH12 retinal organoid model, and we found subtle differences between the WT and mutant at later stages of photoreceptor differentiation. This is in keeping with the milder disease course seen in humans, but it provides insights into the aetiology and possible targets for future therapeutic development.
2025-05-28 | GSE271751 | GEO
Project description:Cone photoreceptor cell death in inherited retinal diseases, such as Retinitis Pigmentosa (RP), leads to the loss of accurate and color vision and ultimately blindness. In RP, a vast number of mutations are affecting the structure and function of rod photoreceptors while cones remain mutation-free. Once majority of rods have degenerated cones are dying secondarily due to the increased oxidative stress, inflammation and loss of structural and nutritional support normally provided by rods. Here we demonstrated that secondary cone cell death in animal models for RP is governed by an increased activity of histone deacetylates (HDACs). A single intravitreal injection of an HDAC inhibitor at a late stage of the disease, when majority of rods have already degenerated, is sufficient to delay cone death and support long-term cone survival. Surviving cones are retaining functionality and are mediating light-driven ganglion cell responses. RNA-seq analysis of surviving cones demonstrated that HDAC inhibition affords multi-level protection trough regulation of different prosurvival pathways including MAPK, PI3K-AKT and autophagy. These study suggest a unique possibility for targeted pharmacological protection of both primary degenerating rods and mutation-free secondary dying cones and creates hope to maintain vision in RP patients independent of the disease stage.
2020-11-04 | GSE141601 | GEO
Project description:Retinitis pigmentosa is the most common hereditary retinal disease. Dietary supplements, neuroprotective agents, cytokines, and lately, prosthetic devices, gene therapy, and optogenetics have been employed to slow down the retinal degeneration or improve light perception. Completing retinal circuitry by transplanting photoreceptors has always been an appealing idea in retinitis pigmentosa. Recent developments in stem cell technology, retinal imaging techniques, tissue engineering, and transplantation techniques have brought us closer to accomplish this goal. The eye is an ideal organ for cell transplantation due to a low number of cells required to restore vision, availability of safe surgical and imaging techniques to transplant and track the cells in vivo, and partial immune privilege provided by the subretinal space. Human embryonic stem cells, induced pluripotential stem cells, and especially retinal organoids provide an adequate number of cells at a desired developmental stage which may maximize integration of the graft to host retina. However, stem cells must be manufactured under strict good manufacturing practice protocols due to known tumorigenicity as well as possible genetic and epigenetic stabilities that may pose a danger to the recipient. Immune compatibility of stem cells still stands as a problem for their widespread use for retinitis pigmentosa. Transplantation of stem cells from different sources revealed that some of the transplanted cells may not integrate the host retina but slow down the retinal degeneration through paracrine mechanisms. Discovery of a similar paracrine mechanism has recently opened a new therapeutic path for reversing the cone dormancy and restoring the sight in retinitis pigmentosa.
| S-EPMC8757529 | biostudies-literature
Project description:Retinitis Pigmentosa (RP) in the human is a progressive, currently irreversible neural degenerative disease usually caused by gene defects that disrupt the function or architecture of the photoreceptors. While RP can initially be a disease of photoreceptors, there is increasing evidence that the inner retina becomes progressively disorganized as the outer retina degenerates. These alterations have been extensively described in animal models, but remodeling in humans has not been as well characterized. This study, using computational molecular phenotyping (CMP) seeks to advance our understanding of the retinal remodeling process in humans. We describe cone mediated preservation of overall topology, retinal reprogramming in the earliest stages of the disease in retinal bipolar cells, and alterations in both small molecule and protein signatures of neurons and glia. Furthermore, while Müller glia appear to be some of the last cells left in the degenerate retina, they are also one of the first cell classes in the neural retina to respond to stress which may reveal mechanisms related to remodeling and cell death in other retinal cell classes. Also fundamentally important is the finding that retinal network topologies are altered. Our results suggest interventions that presume substantial preservation of the neural retina will likely fail in late stages of the disease. Even early intervention offers no guarantee that the interventions will be immune to progressive remodeling. Fundamental work in the biology and mechanisms of disease progression are needed to support vision rescue strategies.
| S-EPMC5031517 | biostudies-literature
Project description:Cone photoreceptor cell death in inherited retinal diseases, such as Retinitis Pigmentosa (RP), leads to the loss of high acuity and color vision and, ultimately to blindness. In RP, a vast number of mutations perturb the structure and function of rod photoreceptors, while cones remain initially unaffected. Extensive rod loss in advanced stages of the disease triggers cone death by a mechanism that is still largely unknown. Here, we show that secondary cone cell death in animal models for RP is associated with increased activity of histone deacetylates (HDACs). A single intravitreal injection of an HDAC inhibitor at late stages of the disease, when the majority of rods have already degenerated, was sufficient to delay cone death and support long-term cone survival in two mouse models for RP, affected by mutations in the phosphodiesterase 6b gene. Moreover, the surviving cones remained light-sensitive, leading to an improvement in visual function. RNA-seq analysis of protected cones demonstrated that HDAC inhibition initiated multi-level protection via regulation of different pro-survival pathways, including MAPK, PI3K-Akt, and autophagy. This study suggests a unique opportunity for targeted pharmacological protection of secondary dying cones by HDAC inhibition and creates hope to maintain vision in RP patients even in advanced disease stages.
| S-EPMC8026998 | biostudies-literature
Project description:Purpose: To identifiy mRNA changes in retinitis pigmentosa (RP) cone photoreceptors with Txnip overexpression treatment, which improved RP cone survival and visual acuity. Methods: two RP mouse strains, rd1 and Rho-/-, were injected with AAV-Txnip or AAV-H2BGFP control subretinally at P0. Retinas were dissected out at P21 for rd1 and P90 for Rho-/-. 1,000 H2BGFP labeled cones per retina sample were FACS sorted out, and subject for RNA-sequencing. Results: >1,400 genes in P21 rd1 and >700 genes in Rho-/- were found differentially expressed with Txnip treatment. Conclusions: 25 genes are in common between P21 rd1 and P90 Rho-/- with Txnip treatment. On this list, notably, three mitochondrial Electron Transport Chain (ETC) genes were up-regulated.
2021-01-20 | GSE161622 | GEO
Project description:PURPOSE:Primary objective-to investigate the effect of retinal vessel oxygen saturation (SO2) on macular oedema (ME) in retinitis pigmentosa (RP) patients. Secondary objective-to link the presence of ME to metabolic (oxygen saturation of retinal vessels, SO2), functional (multifocal electroretinography, mfERG) and structural (Spectral Domain Optical Coherent Tomography, SD-OCT) alterations in RP. DESIGN:Prospective, cross-sectional, non-interventional study. SUBJECTS:Patients with typical RP (N = 37) and controls (N = 19), who underwent retinal vessel Oximetry (RO), SD-OCT and mfERG, were included. METHODS:A computer-based program of the retinal vessel analyser unit (IMEDOS Systems UG, Jena, Germany) was used to measure SO2. We evaluated the mean SO2, in all major retinal arterioles (oxygen saturation in retinal arterioles, A-SO2, %) and venules (oxygen saturation in retinal venules, V-SO2, %). MfERG responses were averaged in zones (zone 1 (0-3°), zone 2 (3-8°) and zone 3 (8-15°)) and compared to corresponding areas of the OCT. The effect of ME on SO2 was evaluated dividing the RP in two subgroups: with clinical appearance of ME (ME-RP) and without it (no-ME-RP). MAIN OUTCOME MEASURES:Parallel recording and juxtaposition of metabolic (SO2) to structural (OCT) and functional-(mfERG) measures. Mean ( ± SD) A-SO2 and V-SO2 were higher in no-ME-RP (96.77% (±6.31) and 59.93% (±7.76)) and even higher in the ME-RP (99.82% (±6.21) and 65.63% (±7.63)), compared to controls (93.15% (±3.76) and 53.77% (±3.70), p ≤ 0.006). RESULTS:The subgroup ME-RP differed significantly from the subgroup no-ME-RP by increased A-SO2 and V-SO2, p ≤ 0.026. The presence of ME confirmed a different relationship between the altered SO2 and the vessel diameters, against the functional and structural parameters. CONCLUSION:Based on our results, the presence of macular oedema indicates a tendency toward greater alteration of the metabolic function in RP patients.
| S-EPMC6043605 | biostudies-literature
Project description:Most mutations in retinitis pigmentosa (RP) arise in rod photoreceptors, but cone photoreceptors, responsible for high-resolution daylight and color vision, are subsequently affected, causing the most debilitating features of the disease. We used mass spectroscopy to follow 13C metabolites delivered to the outer retina and single-cell RNA sequencing to assess photoreceptor transcriptomes. The S cone metabolic transcriptome suggests engagement of the TCA cycle and ongoing response to ROS characteristic of oxidative phosphorylation, which we link to their histone modification transcriptome. Tumor necrosis factor (TNF) and its downstream effector RIP3, which drive ROS generation via mitochondrial dysfunction, are induced and activated as S cones undergo early apoptosis in RP. The long/medium-wavelength (L/M) cone transcriptome shows enhanced glycolytic capacity, which maintains their function as RP progresses. Then, as extracellular glucose eventually diminishes, L/M cones are sustained in long-term dormancy by lactate metabolism.
| S-EPMC10591869 | biostudies-literature
Project description:BackgroundSPATA7 mutations have been associated with different autosomal recessive retinal degeneration phenotypes. Long-term follow-up has not been described in detail.Materials and methodsA Hispanic patient with SPATA7 mutations was evaluated serially over a 12-year period with kinetic and static chromatic perimetry, optical coherence tomography (OCT), and fundus autofluorescence (AF) imaging. Electroretinography (ERG) was performed at the initial visit.ResultsThe patient was homozygous for a mutation in SPATA7 (p.V458fs). At age 9, the ERG showed an abnormally reduced but preserved rod b-wave and no detectable cone signals. There were two islands of vision: a midperipheral island with greater cone than rod dysfunction and a central island with normal cone but no rod function. Serial measures of rod and cone vision and co-localized retinal structure showed that the midperipheral island slowly became undetectable. By age 21, only the central island and its cone function remained, but it had become more abnormal in structure and function.ConclusionThe disease resulting from SPATA7 mutations in this patient initially presented as a cone-rod dystrophy (CRD), but changed over time into a phenotype more reminiscent of late-stage retinitis pigmentosa (RP). The differential diagnosis for both CRD and RP should include this rare molecular cause of autosomal retinal degeneration. An evolving phenotype complicates not only clinical diagnosis and patient counselling but also future strategies aimed at treating specific retinal regions.
| S-EPMC4988809 | biostudies-literature