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QIUPING LIU, FENGJUN ZHANG, LI YU, JINGLIN YI, JINGMING LI; Fenofibrate Attenuates Diabetic Retinopathy by Affecting Nrf2 Expression and NLRP3 Inflammasome Activation. Invest. Ophthalmol. Vis. Sci. 2017;58(8):5227.
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© ARVO (1962-2015); The Authors (2016-present)
Oxidative stress and neuroinflammation contribute significantly to diabetic retinopathy. Fenofibrate has received great attention as treatment of diabetic retinopathy. Nuclear factor erythroid-2-related factor 2 (Nrf2) is a master regulator of anti-oxidative defense. Activation of NLRP3 inflammasome plays a pivotal role in neuroinflammation. The purpose of this study is to evaluate whether fenofibrate ameliorates retinal oxidative damage and neuroinflammation via modulating Nrf2 pathway and blocking NLRP3 inflammasome activation during diabetes.
Diabetes is induced by intraperitoneal injection of streptozotocin in C57BL/6J mice. Fenofibrate were given to mice in rodent chow. Retinal distribution and expression of Nrf2 and NLRP3 were determined by immunofluorescence. Expression of Nrf2-target genes such as HO-1 and NQO-1 were measured by Q-PCR. Retinal oxidative stress were probed with Cellrox, an indicator of reactive oxygen species (ROS). Inflammatory gene expression including pro-caspase-1, caspase-1 p10, pro-IL-1β and IL-1β p17 were examined by western-blot analysis. Retinal leukostasis were evaluated by ConA-lectin staining and vascular leakage were measured by FITC-dextran permeability assay.
Upregulation of Nrf2 and NRLP3 inflammasome, enhanced ROS formation and increased leukostasis and vascular leakage were observed in diabetic mouse retinas. Notably, Nrf2 was mainly colocalized with Muller cell marker-GS; however, NLPR3 and Caspase-1 was prominently colocalzed with Microglia maker-Iba1. Fenofibrate further increased expression of Nrf2 and its target gene HO-1 and NQO-1 and reduced ROS formation in diabetic retinas. In addition, caspase-1 p10 and IL-1β p17 were dramatically increased in diabetic retinas, which were abolished by fenofibrate. Moreover, fenofibrate treatment also attenuated diabetes-induced retinal leukostasis and vascular leakage in mice.
Fenofibrate attenuates oxidative stress and neuroinflammation in diabetic retinas, which is at least partially through modulating Nrf2 expression and NLRP3 inflammasome activation.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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