Salutary effect of fenofibrate on type 1 diabetic retinopathy via inhibiting oxidative stress-mediated Wnt/-βcatenin pathway activation
Salutary effect of fenofibrate on type 1 diabetic retinopathy via inhibiting oxidative stress-mediated Wnt/-βcatenin pathway activation
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DOI：
10.1007/s00441-018-2974-z
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发表时间：
2019-05-01
影响因子：
3.6
通讯作者：
Li, Jingming
中科院分区：
文献类型：
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作者：
Liu, Qiuping;Zhang, Xian;Li, Jingming
非诺贝特已被证明对糖尿病视网膜病变（DR）有治疗作用。我们以前的研究表明，氧化应激激活的Wnt/β-catenin通路在糖尿病并发症中起致病作用。本研究采用C57 BL/6 J-Ins 2（秋田）小鼠遗传性1型糖尿病模型和高糖（HG）处理的ARPE-19小鼠，评价非诺贝特对氧化应激激活的Wnt/β-catenin通路的调节作用及其机制。我们的研究结果表明，视网膜磷酸化LRP 6和核β-连环蛋白增加C57 BL/6 J-Ins 2（秋田）小鼠表明激活Wnt/β-连环蛋白信号。同时，C57 BL/6 J-Ins 2（秋田）显示氧化酶Nox 4和Nox 2的上调以及抗氧化酶SOD 1和SOD 2的下调。所有这些改变在非诺贝特治疗的C57 BL/6 J-Ins 2（秋田）小鼠中逆转。此外，非诺贝特显著改善C57 BL/6 J-Ins 2（秋田）小鼠糖尿病诱导的视网膜血管渗漏。在培养的ARPE-19中，非诺贝特降低HG诱导的Nox 2和Nox 4上调，减弱SOD 1和SOD 2下调，并抑制LRP 6磷酸化。此外，Wnt/β连环蛋白的激活Wnt 3a条件培养基（WCM）减少SOD 1和SOD 2，并不影响Nox 2和Nox 4。非诺贝特抑制WCM诱导的LRP 6磷酸化和逆转SOD下调。重要的是，Nox 4过表达直接磷酸化ARPE 19中的LPR 6;相反，Nox 4敲低抑制HG诱导的LPR 6磷酸化。总之，Nox介导的氧化应激有助于DR中Wnt/β-catenin的激活。非诺贝特通过协调氧化应激的衰减和Wnt/β-catenin信号传导的阻断来改善DR。
Fenofibrate has been shown to have therapeutic effects on diabetic retinopathy (DR). Our previous studies demonstrated that the oxidative stress-activated Wnt/-beta catenin pathway plays a pathogenic role in diabetic complications. In the present study, we evaluate the effect and mechanism of fenofibrate on regulating the oxidative stress-activated Wnt/-beta catenin pathway by using the genetic type 1 diabetes model of C57BL/6J-Ins2(Akita) mice and high glucose (HG)-treated ARPE-19. Our results demonstrated that retinal phosphorylation of LRP6 and nuclear beta-catenin were increased in C57BL/6J-Ins2(Akita) mice suggesting activation of Wnt/-beta catenin signaling. Meanwhile, C57BL/6J-Ins2(Akita) showed upregulation of oxidant enzyme Nox4 and Nox2 and downregulation of antioxidant enzyme SOD1 and SOD2. All these alterations were reversed in C57BL/6J-Ins2(Akita) mice with fenofibrate treatment. Moreover, fenofibrate significantly ameliorated diabetes-induced retinal vascular leakage in C57BL/6J-Ins2(Akita) mice. In cultured ARPE-19, fenofibrate decreased HG-induced Nox2 and Nox4 upregulation, attenuated SOD1 and SOD2 downregulation and inhibited LRP6 phosphorylation. Moreover, activation of Wnt/-beta catenin by Wnt3a conditional medium (WCM) reduced SOD1 and SOD2 and did not affect Nox2 and Nox4. Fenofibrate suppressed WCM-induced LRP6 phosphorylation and reversed SOD downregulation. Importantly, Nox4 overexpression directly phosphorylated LPR6 in ARPE19; conversely, Nox4 knockdown suppressed HG-induced LPR6 phosphorylation. Taken together, Nox-mediated oxidative stress contributes to Wnt/-beta catenin activation in DR. Fenofibrate ameliorated DR through coordinate attenuation of oxidative stress and blockade of Wnt/-beta catenin signaling.