Abstract
Purpose :
Nrf2 is a transcription factor that coordinates anti-oxidant responses to diverse cellular stresses. Nrf2-null mice have increased oxidative stress and are reported to develop age-related retinopathy by 15 months. In conjunction with diabetes, Nrf2-null mice develop blood-retina barrier dysfunction and visual dysfunction. We sought to determine whether glycemic stresses imposed by a high glycemia diet (HG), typical of American diets, in Nrf2-null mice would recapitulate vascular defects and retinopathy and to what degree a low glycemia diet (LG) would be neuroprotective during normal aging.
Methods :
3-month old male Nrf2-null mice were pair fed HG or LG diets until 18 months. Glycemic stress was determined by intraperitoneal glucose tolerance test. Retina pathology was assessed via funduscopy, fluorescein angiography, histology, and electron microscopy. Fundus images and fluorescein angiography images were systematically scored for retinal and vascular phenotypes.
Results :
Nrf2-null mice fed HG diets became overweight, hyperglycemic, and insulin resistant whereas those fed LG diets maintained normal weight and had increased insulin sensitivity. Nrf2-null mice fed a HG diet developed AMD-like features including photoreceptor degeneration, RPE atrophy and hypopigmentation, sub-RPE drusenoid deposits, accumulation of lipofuscin, and loss of choriocapillaris. In contrast, Nrf2-null LG-fed mice did not develop retinopathies and had normal appearing photoreceptors and RPE. Vascular defects were observed in both dietary conditions, including vessel telangiectasia and fluorescein leakage associated with microaneurysms and possible retinal neovascularization. Retinal capillary ischemia was also observed, with more extensive ischemia in HG-fed mice.
Conclusions :
Chronic consumption of a HG diet in Nrf2-null mice induces AMD-like disease earlier and more severely than in WT mice. Despite the absence of Nrf2 function, consumption of a LG diet prevented AMD and dramatically improved glycemic control in Nrf2-null mice. Nrf2-null mice develop defects in their retinal vasculature, which are worsened by glycemic stress. Our studies point to the Nrf2-null mouse as an accelerated mouse model of AMD, and offer insights into mechanisms by which glycemic stress can contribute to both diabetic retinopathy and AMD.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.