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Minghao Jin, Chunfeng Lu, Songhua Li; Intense Light Stress Activated Necrosomes in Wild-Type but not RPE65-Null rd12 Mouse Retina. Invest. Ophthalmol. Vis. Sci. 2021;62(8):2976.
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Photoreceptors in wild-type, but not in RPE65-deficient, mouse degenerate in response to intense light damage. The mechanisms resulting in photoreceptor death or survival in these different genotype mice remain largely unknown. The purpose of this study was to know whether necrosome activation contributes to determination of the different fates of photoreceptors in wild-type and rd12 mice exposed to intense light.
Wild-type 129S2/Sv mice and rd12 mice treated with 9-cis-retinal (a functional iso-chromophore) or vehicle were exposed to 15000 lux light for different times. Photoreceptor degeneration was evaluated by peanut agglutinin (PNA)-staining, immunohistochemistry and immunoblot analysis of opsins. Expression of receptor interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL) in the retinas was analyzed by immunohistochemistry and immunoblot analysis. Activation of MLKL was assessed by detecting its phosphorylation. Correlation between photoreceptor degeneration and RIPK1 expression was determined by Spearman’s correlation analysis. Interaction of the necrosome proteins (RIPK1, RIPK3, and MLKL) was analyzed by double-immunostaining and immunoprecipitation.
Intense light induced a time-dependent rod and cone degeneration as well as gradual upregulation of RIPK1 expression in wild-type mice. Spearman’s correlation analysis showed a negative correlation between photoreceptor degeneration and RIPK1 expression levels in the light exposed wild-type retinas. Intense light stress induced upregulation of RIPK1 in the retinas of rd12 mice treated with 9-cis-retinal, but bot treated with vehicle. Expression of RIPK3 was markedly increased in the wild-type but not rd12 mouse retinas exposed to intense light. Retinal photodamage promoted colocalization and interaction of RIPK1 and RIPK3 in the photoreceptors of wild-type mice. Phosphorylation of MLKL was significantly increased in the wild-type retinas, but not in rd12 retinas, under the same light conditions.
Our results indicate 1. activation of the necrosomes contributed to light-induced photoreceptor degeneration and 2. functional visual pigments are required to activate the necrosomes in the photoreceptors under intense light stress.
This is a 2021 ARVO Annual Meeting abstract.
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