Hsu Ying-Jung, Lin Chao-Wen, Cho Sheng-Li, Yang Wei-Shiung, Yang Chung-May, Yang Chang-Hao
Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, No. 1, Jen Ai Road Section 1, Taipei 100, Taiwan.
Department of Ophthalmology, National Taiwan University Hospital, No. 7, Zhongshan South Road, Taipei 100, Taiwan.
Antioxidants (Basel). 2020 Aug 5;9(8):712. doi: 10.3390/antiox9080712.
Diabetic retinopathy (DR) is an important microvascular complication of diabetes and one of the leading causes of blindness in developed countries. Two large clinical studies showed that fenofibrate, a peroxisome proliferator-activated receptor type α (PPAR-α) agonist, reduces DR progression. We evaluated the protective effects of fenofibrate on retinal/choroidal vascular endothelial cells under oxidative stress and investigated the underlying mechanisms using RF/6A cells as the model system and paraquat (PQ) to induce oxidative stress. Pretreatment with fenofibrate suppressed reactive oxygen species (ROS) production, decreased cellular apoptosis, diminished the changes in the mitochondrial membrane potential, increased the mRNA levels of peroxiredoxin (Prx), thioredoxins (Trxs), B-cell lymphoma 2 (Bcl-2), and Bcl-xl, and reduced the level of B-cell lymphoma 2-associated X protein (Bax) in PQ-stimulated RF/6A cells. Western blot analysis revealed that fenofibrate repressed apoptosis through cytosolic and mitochondrial apoptosis signal-regulated kinase-1 (Ask)-Trx-related signaling pathways, including c-Jun amino-terminal kinase (JNK) phosphorylation, cytochrome c release, caspase 3 activation, and poly (ADP-ribose) polymerase-1 (PARP-1) cleavage. These protective effects of fenofibrate on RF/6A cells may be attributable to its anti-oxidative ability. Our research suggests that fenofibrate could serve as an effective adjunct therapy for ocular oxidative stress-related disorders, such as DR.
糖尿病视网膜病变（DR）是糖尿病重要的微血管并发症，也是发达国家失明的主要原因之一。两项大型临床研究表明，过氧化物酶体增殖物激活受体α（PPAR-α）激动剂非诺贝特可减缓DR的进展。我们评估了非诺贝特在氧化应激下对视网膜/脉络膜血管内皮细胞的保护作用，并以RF/6A细胞为模型系统，用百草枯（PQ）诱导氧化应激，研究其潜在机制。非诺贝特预处理可抑制活性氧（ROS）生成，减少细胞凋亡，减轻线粒体膜电位变化，增加过氧化物还原酶（Prx）、硫氧还蛋白（Trxs）、B细胞淋巴瘤2（Bcl-2）和Bcl-xl的mRNA水平，并降低PQ刺激的RF/6A细胞中B细胞淋巴瘤2相关X蛋白（Bax）的水平。蛋白质免疫印迹分析显示，非诺贝特通过胞质和线粒体凋亡信号调节激酶-1（Ask）-Trx相关信号通路抑制细胞凋亡，包括c-Jun氨基末端激酶（JNK）磷酸化、细胞色素c释放、半胱天冬酶3激活和聚（ADP-核糖）聚合酶-1（PARP-1）裂解。非诺贝特对RF/6A细胞的这些保护作用可能归因于其抗氧化能力。我们的研究表明，非诺贝特可作为眼部氧化应激相关疾病（如DR）的有效辅助治疗药物。
