Cyr61 activates retinal cells and prolongs photoreceptor survival in rd1 mouse model of retinitis pigmentosa

Kucharska, Joanna; Río, Patricia del; Ueffing, Marius; Gorza, Matteo; Feuchtinger, Annette; Hauck, Stefanie M.; Ueffing, Marius

doi:10.1111/jnc.12704

Cited by 18 publications

(15 citation statements)

References 79 publications

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“…46 To circumvent these issues, we cultured RPE-free retinal explants in total darkness after harvesting from dark-adapted mice. Recently improved explants methods have been introduced, 47–49 but, in contrast to those techniques, our approach cultured and harvested the explants in the dark, which improved their viability under our conditions. Using our procedure and placing the retinas photoreceptor-side-up, we were able to maintain photoreceptor viability, structure, and function for at least 7 days.…”

Section: Discussionmentioning

confidence: 99%

Molecular Pathway to Protection From Age-Dependent Photoreceptor Degeneration in Mef2 Deficiency

Nagar

Trudler

McKercher

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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PurposePhotoreceptor degeneration in the retina is a major cause of blindness in humans. Elucidating mechanisms of degenerative and neuroprotective pathways in photoreceptors should afford identification and development of therapeutic strategies.MethodsWe used mouse genetic models and improved methods for retinal explant cultures. Retinas were enucleated from Mef2d+/+ and Mef2d−/− mice, stained for MEF2 proteins and outer nuclear layer thickness, and assayed for apoptotic cells. Chromatin immunoprecipitation (ChIP) assays revealed MEF2 binding, and RT-qPCR showed levels of transcription factors. We used AAV2 and electroporation to express genes in retinal explants and electroretinograms to assess photoreceptor functionality.ResultsWe identify a prosurvival MEF2D-PGC1α pathway that plays a neuroprotective role in photoreceptors. We demonstrate that Mef2d−/− mouse retinas manifest decreased expression of PGC1α and increased photoreceptor cell loss, resulting in the absence of light responses. Molecular repletion of PGC1α protects Mef2d−/− photoreceptors and preserves light responsivity.ConclusionsThese results suggest that the MEF2-PGC1α cascade may represent a new therapeutic target for drugs designed to protect photoreceptors from developmental- and age-dependent loss.

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Section: Discussionmentioning

confidence: 99%

Molecular Pathway to Protection From Age-Dependent Photoreceptor Degeneration in Mef2 Deficiency

Nagar

Trudler

McKercher

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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“…Despite previous evidence that CYR61 is associated with neuroprotection in a mouse model of retinitis pigmentosa (Kucharska et al . ), increased endogenous Cyr61 expression is usually observed under pathological conditions and can be induced experimentally by stimuli that cause cellular stress (i.e. inflammation) (Malik et al .…”

Section: Discussionmentioning

confidence: 99%

Widespread brain transcriptome alterations underlie the neuroprotective actions of dietary saffron

Skladnev

Ganeshan

Kim

et al. 2016

Journal of Neurochemistry

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Dietary saffron has shown promise as a neuroprotective intervention in clinical trials of retinal degeneration and dementia and in animal models of multiple CNS disorders, including Parkinson's disease. This therapeutic potential makes it important to define the relationship between dose and protection and the mechanisms involved. To explore these two issues, mice were pre-conditioned by providing an aqueous extract of saffron (0.01% w/v) as their drinking water for 2, 5 or 10 days before administration of the parkinsonian neurotoxin MPTP (50 mg/kg). Five days of saffron pre-conditioning provided the greatest benefit against MPTP-induced neuropathology, significantly mitigating both loss of functional dopaminergic cells in the substantia nigra pars compacta (p < 0.01) and abnormal neuronal activity in the caudate-putamen complex (p < 0.0001). RNA microarray analysis of the brain transcriptome of mice pre-conditioned with saffron for 5 days revealed differential expression of 424 genes. Bioinformatics analysis identified enrichment of molecular pathways (e.g. adherens junction, TNFR1 and Fas signaling) and expression changes in candidate genes (Cyr61, Gpx8, Ndufs4, and Nos1ap) with known neuroprotective actions. The apparent biphasic nature of the dose-response relationship between saffron and measures of neuroprotection, together with the stress-inducible nature of many of the up-regulated genes and pathways, lend credence to the idea that saffron, like various other phytochemicals, is a hormetic stimulus, with functions beyond its strong antioxidant capacity. These findings provide impetus for a more comprehensive evaluation of saffron as a neuroprotective intervention.

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“…Study by You [20] stated that Cyr61 induced expression of VEGF and vice versa, and anti-Cyr61 or anti-VEGF could inhibit the effects of both Cyr61 and VEGF. On the other hand, as an endogenous pro-survival factor for photoreceptors, elevated Cyr61 could contribute to the complex repertoire of neuroprotective activities generated by RMG and RPE cells [27] .…”

Section: Discussionmentioning

confidence: 99%

Potential Role of Cyr61 Induced Degeneration of Human Müller Cells in Diabetic Retinopathy

et al. 2014

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The degeneration of Müller cells has been recognized to involve in the pathogenesis of diabetic retinopathy. However, the mechanism is not yet clear. This study is to explore the potential role of Cyr61, a secreted signaling protein in extracellular matrix, in inducing human Müller cell degeneration in diabetic retinopathy (DR). Twenty patients with proliferative diabetic retinopathy (PDR) and twelve non-diabetic patients were recruited for this study. Vitreous fluid was collected during vitrectomy surgery for Cyr61 ELISA. Human Müller cell line MIO-M1 were cultured to be subconfluent, and then treated with glucose (0–20 mM) or Cyr61 (0–300 ng/ml). Cyr61 expression induced by increasing concentrations of glucose was evaluated by RT-qPCR and Western blot. Effects of Cyr61 on Müller cells viability, migration and apoptosis were observed by MTT assay, Transwell assay, and TUNEL assay. Vitreous Cyr61 levels were observed to be 8-fold higher in patients with PDR (3576.92±1574.58 pg/mL), compared with non-diabetic controls (436.14±130.69 pg/mL). Interestingly, the active PDR group was significantly higher than the quiescent PDR group (P<0.01). In retinal Müller cells culture, high glucose significantly and dose-dependently elevated Cyr61 expression at both mRNA and protein levels. Cyr61 at high concentrations dose-dependently inhibited the viability and migration of Müller cells. TUNEL assay further revealed that high concentration of Cyr61 significantly promoted the cell apoptosis. In conclusion, these findings demonstrated for the first time that the expression of Cyr61 was elevated by high glucose in Müller cells, and Cyr61 inhibited cell viability and migration while induced apoptosis, suggesting the potential role of Cyr61 in Müller cell degeneration. The elevated Cyr61 levels in vitreous fluid of PDR patients further support its role in diabetic retinopathy (DR).

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Cyr61 activates retinal cells and prolongs photoreceptor survival in rd1 mouse model of retinitis pigmentosa

Cited by 18 publications

References 79 publications

Molecular Pathway to Protection From Age-Dependent Photoreceptor Degeneration in Mef2 Deficiency

Molecular Pathway to Protection From Age-Dependent Photoreceptor Degeneration in Mef2 Deficiency

Widespread brain transcriptome alterations underlie the neuroprotective actions of dietary saffron

Potential Role of Cyr61 Induced Degeneration of Human Müller Cells in Diabetic Retinopathy

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