Hyperactivation of retina by light in mice leads to photoreceptor cell death mediated by VEGF and retinal pigment epithelium permeability

Cachafeiro, M. Carmen Blanco; Bemelmans, Alexis-Pierre; Samardzija, Marijana; Afanasieva, Tatiana A.; Ja, Pournaras; Grimm, Christian; Kostic, Corinne; Philippe, Stéphanie; Wenzel, Andreas; Arsenijévic, Yvan

doi:10.1038/cddis.2013.303

Cited by 53 publications

(45 citation statements)

References 53 publications

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“…Recent studies show that RPE is adversely affected by light exposure (48). We observed the involvement of the RPE in the phagocytosis of GCAP1 and rhodopsin-positive membranes (Fig.…”

Section: Our Findings On Arr1mentioning

confidence: 50%

Induction of the Unfolded Protein Response by Constitutive G-protein Signaling in Rod Photoreceptor Cells

Chen

2014

Journal of Biological Chemistry

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Background: Excessive light exposure and genetic mutations that act as "equivalent light" cause photoreceptor cell death. Results: Prolonged transducin signaling, but not channel closure, induces endoplasmic reticulum stress. Conclusion: Induction of UPR is a distinct cell death pathway caused by transducin signaling. Significance: Manipulation of UPR may prolong photoreceptor cell survival in transducin-induced retinal light damage.

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“…Recent studies show that RPE is adversely affected by light exposure (48). We observed the involvement of the RPE in the phagocytosis of GCAP1 and rhodopsin-positive membranes (Fig.…”

Section: Our Findings On Arr1mentioning

confidence: 50%

Induction of the Unfolded Protein Response by Constitutive G-protein Signaling in Rod Photoreceptor Cells

Chen

2014

Journal of Biological Chemistry

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“…It has been shown that hyper-activation of the retina via bright-light exposure leads to photoreceptor cell death in mice due, in part, to increased VEGF-mediated RPE permeability [39]. To investigate the effects of the αCT1 peptide on RPE cell integrity, RPE damage was triggered using a light-damage model (3000 lux of white light for 3 hours) in Balb/c mice.…”

Section: Resultsmentioning

confidence: 99%

Targeting the tight junction protein, zonula occludens-1, with the connexin43 mimetic peptide, αCT1, reduces VEGF-dependent RPE pathophysiology

et al. 2017

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A critical target tissue in age-related macular degeneration (AMD) is the retinal pigment epithelium (RPE), which forms the outer blood-retina barrier (BRB). RPE-barrier dysfunction might result from attenuation/disruption of intercellular tight junctions. Zonula occludens-1 (ZO-1) is a major structural protein of intercellular junctions. A connexin43-based peptide mimetic, αCT1 was developed to competitively block interactions at the PDZ2 domain of ZO-1, thereby inhibiting ligands that selectively bind to this domain. We hypothesized that targeting ZO-1 signaling using αCT1 would maintain BRB integrity and reduce RPE pathophysiology by stabilizing gap- and/or tight-junctions. RPE-cell barrier dysfunction was generated in mice using laser-photocoagulation triggering choroidal neovascularization (CNV), or bright-light exposure leading to morphological damage. αCT1 was delivered via eyedrops. αCT1 treatment reduced CNV development and fluid leakage as determined by optical coherence tomography, and damage was correlated with disruption in cellular integrity of surrounding RPE cells. Light-damage significantly disrupted RPE cell morphology as determined by ZO-1 and Occludin staining and tiling pattern analysis, which was prevented by αCT1 pre-treatment. In vitro experiments using RPE and MDCK monolayers indicated that αCT1 stabilizes tight junctions, independent of its effects on Cx43. Taken together, stabilization of intercellular junctions by αCT1 was effective in ameliorating RPE dysfunction in models of AMD-like pathology.

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“…In albino BALB/c mice, spatial visual acuity was under the limit of detection already at baseline, even before exposure to SI, so this functional measure could not be followed in this strain (similar absent or severely reduced OKT responses in albino mice have been previously reported by others). [30][31][32] Electrophysiological Retinal Function…”

Section: Optimizing Intraperitoneal Sodium Iodate Dosementioning

confidence: 99%

Course of Sodium Iodate–Induced Retinal Degeneration in Albino and Pigmented Mice

Chowers

Cohen

Marks-Ohana

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. To characterize the course of sodium iodate (SI)-induced retinal degeneration in young adult albino and pigmented mice. (25, 50, and 100 mg/kg) were performed in 7-to 8-week-old BALB/c and C57Bl/6J mice. Retinal function and structure was assessed at baseline, 24 hours, 3 days, 1, 2, 3, and 4 weeks postinjection by optokinetic tracking response, ERG, optical coherence tomography (OCT), and histologic and immunohistochemical techniques. METHODS. Single intraperitoneal (IP) injections of SI RESULTS.The 50 mg/kg SI dosage was selected after dose ranging due to consistent retinal effects and lack of systemic toxicity. Time-dependent deterioration in retinal function and morphology was consistently observed between 1 and 4 weeks in all measured parameters. These include reduction of ERG responses, thinning of retinal layers as observed by OCT and histology, and loss of RPE nuclei. Immunohistochemistry revealed rapid RPE disorganization with loss of tight junctions and markedly reduced expression of RPE65 and rod opsin, accompanied by mislocalization of cone opsins. Earlier time points displayed variable results, including partial recovery of visual acuity at 1 week and supranormal ERG cone responses at 24 hours, suggesting possible limitations of early intervention and assessment in the SI model. CONCLUSIONS.A single IP injection of 50 mg/kg SI leads to severe RPE injury followed by vision impairment, dysfunction, and loss of photoreceptors in both BALB/c and C57Bl/6J mice. This easily induced and reproducible noninherited model may serve as a useful tool for seeking and evaluating novel therapeutic modalities for the treatment of retinal degenerations caused by primary failure of the RPE.Keywords: sodium iodate, RPE toxicity, retinal degeneration, mouse model D iseases such as AMD, Best disease, and subtypes of retinitis pigmentosa RP are major causes of visual disability. 1 In these diseases, primary dysfunction, degeneration, and loss of the RPE ultimately results in secondary death of photoreceptors, leading to visual loss. [2][3][4] Despite certain progress in the treatment of retinal degeneration, it remains an essentially irreversible process in which many patients eventually lose their sight. Animal models provide an invaluable tool for searching and testing of novel therapeutic modalities. Animals carrying natural mutations (usually in one gene) provide well-established models for inherited retinal diseases. 5,6 However, the pathogenesis of multifactorial retinal degenerations such as AMD involves complex genetic and environmental factors, leading to expression of disease at older ages. 7 The majority of geneticallyinherited animal models of ocular disease do not entirely mimic such conditions because of early disease onset and progression. 8 Regardless of etiology, maintaining proper RPE function is a major therapeutic target in these diseases, and currently pharmaceutical, genetic, and cellular approaches are being tested to this end in a variety of in vitro and in vivo models, as well as in clini...

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Hyperactivation of retina by light in mice leads to photoreceptor cell death mediated by VEGF and retinal pigment epithelium permeability

Cited by 53 publications

References 53 publications

Induction of the Unfolded Protein Response by Constitutive G-protein Signaling in Rod Photoreceptor Cells

Induction of the Unfolded Protein Response by Constitutive G-protein Signaling in Rod Photoreceptor Cells

Targeting the tight junction protein, zonula occludens-1, with the connexin43 mimetic peptide, αCT1, reduces VEGF-dependent RPE pathophysiology

Course of Sodium Iodate–Induced Retinal Degeneration in Albino and Pigmented Mice

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