ANGPTL-4 induces diabetic retinal inflammation by activating Profilin-1
ANGPTL-4 induces diabetic retinal inflammation by activating Profilin-1
复制标题
ANGPTL-4通过激活Profilin-1诱导糖尿病视网膜炎症
DOI：
10.1016/j.exer.2017.10.009
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发表时间：
2018-01-01
影响因子：
3.4
通讯作者：
Zheng, Zhi
中科院分区：
文献类型：
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作者：
Lu, Qianyi;Lu, Peirong;Zheng, Zhi
糖尿病视网膜病变(DR)是导致工作年龄成年人不可逆性失明的最常见原因，它会导致中心视力丧失，这是由于眼后视网膜的微血管损伤造成的。这项工作的目的是评估血管生成素样蛋白-4(ANGPTL-4)，一种新的脂肪细胞因子，与糖尿病视网膜炎症和微血管功能障碍之间的时间关系。在高糖(HG)条件下测定ANGPTL-4的下游途径(S)和上游介体(S)。糖尿病大鼠和对照组动物随机分为低氧诱导因子-1α(HIF-1α)阻断剂(阿霉素或shRNA)或赋形剂治疗8周。人视网膜微血管内皮细胞(HRMECs)与正常或高糖、有或无阻断或重组蛋白孵育，表达血管内皮细胞生长因子(VEGF)、血管内皮生长因子-4(ANGPTL-4)、缺氧诱导因子-1α(HIF-1α)。用Western blotting和实时定量RT-PCR方法检测大鼠视网膜和HRMEC提取液中ANGPTL-4、Profllin-1、HIF-1α、VEGF、IL-1β、IL-6和细胞间黏附分子-1(ICAM-1)的表达水平。糖尿病大鼠和汞暴露的HRMECs中ANGPTL-4、Profllin-1、HIF-1α和血管内皮生长因子的蛋白和mRNA水平显著升高。ANGPTL-4是一种通过激活Profilin-1信号通路来增加炎症、通透性和血管生成的有效调节剂。我们的结果表明，无论在体内还是在体外，HG都能诱导ANGPTL-4的上调，这依赖于HIF-1α的激活，而HIF-1α的激活也是由HG触发的。我们的结果表明，靶向ANGPTL-4，单独或联合Profilin-1，可能是增殖性糖尿病视网膜病变和其他玻璃体-视网膜炎症性疾病的有效治疗策略和诊断筛查生物标志物。
Diabetic retinopathy (DR), the most common cause of irreversible blindness in working-age adults, results in central vision loss that is caused by microvascular damage to the inner lining of the back of the eye, the retina. The aim of this work was to assess the temporal relationships between angiopoietin-like protein-4 (ANGPTL-4), a novel adipocytokine factor, and diabetic retinal inflammation and microvascular dysfunction. The downstream pathway(s) and upstream mediator(s) of ANGPTL-4 were then determined under high glucose (HG) conditions. Diabetic rats and control animals were randomly assigned to receive hypoxia inducible factor-1 alpha (HIF-1 alpha) blockade (doxorubicin or shRNA) or vehicle for 8 weeks. Human retinal microvascular endothelial cells (HRMECs) were incubated with normal or high glucose, with or without blockade or recombinant proteins, for ANGPTL-4, HIF-1 alpha, and vascular endothelial growth factor (VEGF). The levels of ANGPTL-4, profllin-1, HIF-1 alpha, VEGF, interleukin 1 beta (IL-1 beta), IL-6, and intercellular adherent molecule 1 (ICAM-1) in the rat retinas and HRMEC extracts were examined by Western blotting and real-time RT-PCR. The levels of ANGPTL-4, profllin-1, HIF-1 alpha, and VEGF protein and mRNA were significantly higher in the diabetic rats and HG-exposed HRMECs. ANGPTL-4 was a potent modulator of increased inflammation, permeability, and angiogenesis via activation of the profilin-1 signaling pathway. Our results showed that ANGPTL-4 upregulation was induced by HG, which was dependent on HIF-1 alpha activation that was also triggered by HG, both in vivo and in vitro. Our results suggest that targeting ANGPTL-4, alone or in combination with profilin-1, may be an effective therapeutic strategy and diagnostic screening biomarker for proliferative diabetic retinopathy and other vitreous-retinal inflammatory diseases.