Fenofibrate ameliorates diabetic retinopathy by modulating Nrf2 signaling and NLRP3 inflammasome activation
Fenofibrate ameliorates diabetic retinopathy by modulating Nrf2 signaling and NLRP3 inflammasome activation
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非诺贝特通过调节 Nrf2 信号传导和 NLRP3 炎性体激活改善糖尿病视网膜病变
DOI：
10.1007/s11010-017-3256-x
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发表时间：
2018-08-01
影响因子：
4.3
通讯作者：
Li, Jingming
中科院分区：
文献类型：
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作者：
Liu, Qiuping;Zhang, Fengjun;Li, Jingming
氧化应激和神经炎症对糖尿病视网膜病变的发生和进展有显着影响。非诺贝特因其通过减少视网膜激光需求而使糖尿病患者受益而受到广泛关注。核因子红细胞 2 相关因子 2 (Nrf2) 是抗氧化防御的主要调节因子。核苷酸结合域、富含亮氨酸重复序列的受体 (NLR)、含吡啶结构域 3 (NLRP3) 炎症小体的激活在神经炎症中发挥着关键作用。本研究的目的是确定非诺贝特是否在糖尿病期间通过调节 Nrf2 通路和阻断 NLRP3 炎症小体激活来保护视网膜免受氧化损伤和神经炎症。小鼠腹腔注射链脲佐菌素可诱发糖尿病。非诺贝特被给予啮齿类动物饲料中的小鼠。在糖尿病小鼠视网膜中观察到 Nrf2 和 NLRP3 炎性体的上调、ROS 形成增强、白细胞停滞和血管渗漏增加。值得注意的是，Nrf2 和 Caspase-1 主要与谷氨酰胺合成酶（Mşller 细胞标记物之一）共定位。非诺贝特进一步增加了 Nrf2 及其靶基因 NQO-1 和 HO-1 的表达，并减少了糖尿病视网膜中 ROS 的形成。此外，在媒介物治疗的糖尿病小鼠中，NLRP3、Caspase-1 p20、IL-1β p17 和 ICAM-1 的视网膜表达显着增加，但通过非诺贝特干预消除了这种表达。此外，非诺贝特治疗还减轻了糖尿病引起的小鼠视网膜白细胞停滞和血管渗漏。总而言之，非诺贝特可减轻糖尿病视网膜中的氧化应激和神经炎症，这至少部分是通过调节 Nrf2 表达和 NLRP3 炎症小体激活来实现的。
Oxidative stress and neuroinflammation contribute significantly to the development and progression of diabetic retinopathy. Fenofibrate has received great attention as it benefits diabetic patients by reducing retinal laser requirement. Nuclear factor erythroid-2-related factor 2 (Nrf2) is a master regulator of anti-oxidative defense. Activation of nucleotide binding domain, leucine-rich repeat-containing receptor (NLR), pyrin domain-containing 3 (NLRP3) inflammasome plays a pivotal role in neuroinflammation. The purpose of this study is to determine whether fenofibrate protects retinas from oxidative damage and neuroinflammation via modulating the Nrf2 pathway and blocking NLRP3 inflammasome activation during diabetes. Diabetes is induced by intraperitoneal injection of streptozotocin in mice. Fenofibrate was given to mice in rodent chow. Upregulation of Nrf2 and NLRP3 inflammasome, enhanced ROS formation, and increased leukostasis and vascular leakage were observed in diabetic mouse retinas. Notably, Nrf2 and Caspase-1 were mainly colocalized with glutamine synthetase, one of the Mȕller cell markers. Fenofibrate further increased the expression of Nrf2 and its target gene NQO-1 and HO-1 and reduced ROS formation in diabetic retinas. In addition, retinal expression of NLRP3, Caspase-1 p20, IL-1β p17, and ICAM-1 were dramatically increased in vehicle-treated diabetic mice, which were abolished by fenofibrate intervention. Moreover, fenofibrate treatment also attenuated diabetes-induced retinal leukostasis and vascular leakage in mice. Taken together, fenofibrate attenuates oxidative stress and neuroinflammation in diabetic retinas, which is at least partially through modulating Nrf2 expression and NLRP3 inflammasome activation.