Enright Jennifer M, Zhang Sheng, Thebeau Christina, Siebert Emily, Jin Alexander, Gadiraju Veda, Zhang Xiaodong, Chen Shiming, Semenkovich Clay F, Rajagopal Rithwick
John F. Hardesty Department of Ophthalmology, Washington University in St. Louis, St. Louis, MO 63110, USA.
Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX 75390, USA.
J Clin Med. 2020 Dec 31;10(1):126. doi: 10.3390/jcm10010126.
Fenofibrate slows the progression of clinical diabetic retinopathy (DR), but its mechanism of action in the retina remains unclear. Fenofibrate is a known agonist of peroxisome proliferator-activated receptor alpha (PPARα), a transcription factor critical for regulating metabolism, inflammation and oxidative stress. Using a DR mouse model, , we tested the hypothesis that fenofibrate slows early DR progression by activating PPARα in the retina. Relative to healthy littermates, six-month-old mice exhibited elevated serum triglycerides and cholesterol, retinal gliosis, and electroretinography (ERG) changes including reduced b-wave amplitudes and delayed oscillatory potentials. These pathologic changes in the retina were improved by oral fenofibrate. However, fenofibrate did not induce PPARα target gene expression in whole retina or isolated Müller glia. The capacity of the retina to respond to PPARα was further tested by delivering the PPARα agonist GW590735 to the intraperitoneal or intravitreous space in mice carrying the peroxisome proliferator response element (PPRE)-luciferase reporter. We observed strong induction of the reporter in the liver, but no induction in the retina. In summary, fenofibrate treatment of / mice prevents the development of early DR but is not associated with induction of PPARα in the retina.
非诺贝特可减缓临床糖尿病视网膜病变（DR）的进展，但其在视网膜中的作用机制仍不清楚。非诺贝特是过氧化物酶体增殖物激活受体α（PPARα）的已知激动剂，PPARα是一种对调节代谢、炎症和氧化应激至关重要的转录因子。我们使用DR小鼠模型，检验了非诺贝特通过激活视网膜中的PPARα来减缓早期DR进展的假说。与健康同窝小鼠相比，6个月大的小鼠血清甘油三酯和胆固醇升高，视网膜发生胶质增生，并且视网膜电图（ERG）出现变化，包括b波振幅降低和振荡电位延迟。口服非诺贝特可改善视网膜中的这些病理变化。然而，非诺贝特并未在整个视网膜或分离的Müller胶质细胞中诱导PPARα靶基因表达。通过将PPARα激动剂GW590735递送至携带过氧化物酶体增殖物反应元件（PPRE）-荧光素酶报告基因的小鼠的腹腔或玻璃体内，进一步测试了视网膜对PPARα的反应能力。我们观察到报告基因在肝脏中强烈诱导，但在视网膜中未诱导。总之，用非诺贝特治疗小鼠可预防早期DR的发展，但与视网膜中PPARα的诱导无关。
