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Yazhou Qin, Jingming Li, Xian Zhang, Qiuping Liu; Caspase-1 Cleaves LRP6 for Wnt/β-catenin Activation in Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2020;61(7):281.
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Diabetic retinopathy (DR) is a low-grade inflammatory disease characterized by retinal vascular hyper-permeability and pathological neovascularization. Caspase-1 cleaves multiple substrates to mediate a variety of inflammatory cascades. Meanwhile, LRP6/β-catenin pathway plays a causal role in retinal microvasculopathy during DR. Here we hypothesize that caspase-1 contributes to retinal β-catenin activation and inflammatory response by cleaving LRP6 in DR.
Animal models of streptozotocin (STZ)-induced diabetes and oxygen-induced retinopathy (OIR) were set up with both wild type mice and Capsase-1 deficient mice. Retinal vascular leakage, leukostasis and neovascularization were measured by Evan’s blue method, ConA-lectin perfusion and isolectin IB4 staining, respectively. Expression of truncated LRP6, β-catenin and inflammatory cytokines were determined by western-blot analysis or quantitative RT-PCR.
Retinal expression of active caspase-1 p20 were significantly increased in wild type STZ mice and OIR mice. Meanwhile, increased vascular leakage, adherent leukocytes and aberrant neovascularization were observed retinas of wild-type STZ and OIR mice. However, retinal vascular hyper-permeability, increased vascular leukostasis and pathological neovascularization were significantly ameliorated in Caspase-1 deficient mice. Moreover, Caspase-1 deficient STZ and OIR mice displayed attenuated LRP6 truncation, reduced β-catenin accumulation and down-regulated inflammatory gene expression.
Taken together, these results provide in vivo evidence that Caspase-1 deficiency protects against DR likely through suppression of LRP6/β-catenin activation.
This is a 2020 ARVO Annual Meeting abstract.
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