Miller William P, Yang Chen, Mihailescu Maria L, Moore Joshua A, Dai Weiwei, Barber Alistair J, Dennis Michael D
Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA.
Department of Ophthalmology, Penn State College of Medicine, Hershey, PA.
Diabetes. 2018 Jan;67(1):110-119. doi: 10.2337/db17-0728. Epub 2017 Oct 26.
Diabetes-induced visual dysfunction is associated with significant neuroretinal cell death. The current study was designed to investigate the role of the Protein Regulated in Development and DNA Damage Response 1 (REDD1) in diabetes-induced retinal cell death and visual dysfunction. We recently demonstrated that REDD1 protein expression was elevated in response to hyperglycemia in the retina of diabetic rodents. REDD1 is an important regulator of Akt and mammalian target of rapamycin and as such plays a key role in neuronal function and survival. In R28 retinal cells in culture, hyperglycemic conditions enhanced REDD1 protein expression concomitant with caspase activation and cell death. By contrast, in REDD1-deficient R28 cells, neither hyperglycemic conditions nor the absence of insulin in culture medium were sufficient to promote cell death. In the retinas of streptozotocin-induced diabetic mice, retinal apoptosis was dramatically elevated compared with nondiabetic controls, whereas no difference was observed in diabetic and nondiabetic REDD1-deficient mice. Electroretinogram abnormalities observed in b-wave and oscillatory potentials of diabetic wild-type mice were also absent in REDD1-deficient mice. Moreover, diabetic wild-type mice exhibited functional deficiencies in visual acuity and contrast sensitivity, whereas diabetic REDD1-deficient mice had no visual dysfunction. The results support a role for REDD1 in diabetes-induced retinal neurodegeneration.
糖尿病引起的视觉功能障碍与显著的神经视网膜细胞死亡有关。本研究旨在探讨发育和DNA损伤反应调节蛋白1(REDD1)在糖尿病诱导的视网膜细胞死亡和视觉功能障碍中的作用。我们最近证明,在糖尿病啮齿动物的视网膜中,REDD1蛋白表达会因高血糖而升高。REDD1是Akt和雷帕霉素哺乳动物靶点的重要调节因子,因此在神经元功能和存活中起关键作用。在培养的R28视网膜细胞中,高血糖条件会增强REDD1蛋白表达,并伴随半胱天冬酶激活和细胞死亡。相比之下,在缺乏REDD1的R28细胞中,高血糖条件和培养基中缺乏胰岛素都不足以促进细胞死亡。在链脲佐菌素诱导的糖尿病小鼠视网膜中,与非糖尿病对照组相比,视网膜细胞凋亡显著增加,而在糖尿病和非糖尿病REDD1缺陷小鼠中未观察到差异。在REDD1缺陷小鼠中也未观察到糖尿病野生型小鼠在b波和振荡电位中出现的视网膜电图异常。此外,糖尿病野生型小鼠表现出视力和对比敏感度的功能缺陷,而糖尿病REDD1缺陷小鼠没有视觉功能障碍。这些结果支持REDD1在糖尿病诱导的视网膜神经退行性变中的作用。