Rationale: Vasoregression secondary to glial activation develops in various retinal diseases, including retinal degeneration and diabetic retinopathy. Photoreceptor degeneration and subsequent retinal vasoregression, characterized by pericyte loss and acellular capillary formation in the absence diabetes, are also seen in transgenic rats expressing the polycystic kidney disease (PKD) gene. Activated Müller glia contributes to retinal vasodegeneration, at least in part via the expression of the soluble epoxide hydrolase (sEH). Given that an increase in sEH expression triggered vascular destabilization in diabetes, and that vasoregression is similar in diabetic mice and PKD rats, the aim of the present study was to determine whether sEH inhibition could prevent retinal vasoregression in the PKD rat./nMethods: One-month old male homozygous transgenic PKD rats were randomly allocated to receive vehicle or a sEH inhibitor (sEH-I; Sar5399, 30 mg/kg) for four weeks. Wild-type Sprague-Dawley (SD) littermates received vehicle as controls. Retinal sEH expression and activity were measured by Western blotting and LC-MS, and vasoregression was quantified in retinal digestion preparations. Microglial activation and immune response cytokines were assessed by immunofluorescence and quantitative PCR, respectively. 19,20-dihydroxydocosapentaenoic acid (19,20-DHDP) mediated Notch signaling, microglial activation and migration were assessed in vivo and in vitro./nResults: This study demonstrates that sEH expression and activity were increased in PKD retinae, which led to elevated production of 19,20-DHDP and the depression of Notch signaling. The latter changes elicited pericyte loss and the recruitment of CD11b⁺/CD74⁺ microglia to the perivascular region. Microglial activation increased the expression of immune-response cytokines, and reduced levels of Notch3 and delta-like ligand 4 (Dll4). Treatment with Sar5399 decreased 19,20-DHDP generation and increased Notch3 expression. Sar5399 also prevented vasoregression by reducing pericyte loss and suppressed microglial activation as well as the expression of immune-response cytokines. Mechanistically, the activation of Notch signaling by Dll4 maintained a quiescent microglial cell phenotype, i.e. reduced both the surface presentation of CD74 and microglial migration. In contrast, in retinal explants, 19,20-DHDP and Notch inhibition both promoted CD74 expression and reversed the Dll4-induced decrease in migration./nConclusions: Our data indicate that 19,20-DHDP-induced alterations in Notch-signaling result in microglia activation and pericyte loss and contribute to retinal vasoregression in polycystic kidney disease. Moreover, sEH inhibition can ameliorate vasoregression through reduced activity of inflammatory microglia. sEH inhibition is thus an attractive new therapeutic approach to prevent retinal vasoregression.

中文翻译：

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可溶性环氧水解酶抑制作用在与多囊肾有关的视网膜血管病变中的保护作用。

理由：神经胶质活化继发的血管收缩在多种视网膜疾病中发展，包括视网膜变性和糖尿病性视网膜病。在表达多囊性肾病（PKD）基因的转基因大鼠中，也可见光感受器变性和随后的视网膜血管退化，其特征是在缺乏糖尿病的情况下细胞减少和无细胞毛细血管形成。激活的Müller胶质细胞至少部分通过可溶性环氧化物水解酶（sEH）的表达促进视网膜血管生成。鉴于sEH表达的增加触发了糖尿病中的血管失稳，并且糖尿病小鼠和PKD大鼠的血管收缩相似，因此本研究的目的是确定sEH抑制作用是否可以预防PKD大鼠的视网膜血管收缩./n方法：将一个月大的雄性纯合转基因PKD大鼠随机分配为接受媒介物或sEH抑制剂（sEH-1； Sar5399，30 mg / kg）4周。野生型Sprague-Dawley（SD）同窝仔接受媒介物作为对照。通过Western印迹和LC-MS测量视网膜sEH的表达和活性，并在视网膜消化制剂中定量血管收缩。小胶质细胞活化和免疫反应细胞因子分别通过免疫荧光和定量PCR进行评估。19,20-dihydroxydocosapentaenoic酸（19,20-DHDP）介导的Notch信号传导，小胶质细胞活化和迁移进行了评估在体内和体外./n结果：这项研究表明PKD视网膜中sEH的表达和活性增加，从而导致19,20-DHDP的产量增加和Notch信号的降低。后者的变化引起周细胞丢失，并募集CD11b ⁺ / CD74 ⁺小胶质细胞到血管周围区域。小胶质细胞激活增加了免疫应答细胞因子的表达，并降低了Notch3和δ样配体4（Dll4）的水平。Sar5399处理可减少19,20-DHDP生成并增加Notch3表达。Sar5399还通过减少周细胞损失和抑制小胶质细胞活化以及免疫反应细胞因子的表达来预防血管退化。从机理上讲，Dll4对Notch信号的激活维持了静止的小胶质细胞表型，即减少了CD74的表面表现和小胶质细胞迁移。相反，在视网膜外植体中，19,20-DHDP和Notch抑制均能促进CD74表达并逆转Dll4诱导的迁移减少。/n结论：我们的数据表明19,20-DHDP诱导的Notch信号改变导致小胶质细胞活化和周细胞损失，并在多囊性肾脏疾病中导致视网膜血管退化。此外，sEH抑制可通过降低炎症性小胶质细胞的活性来改善血管收缩。因此，sEH抑制是防止视网膜血管退化的一种有吸引力的新治疗方法。