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Sheldon Rowan, Shuhong Jiang, Min-Lee Chang, Naila Rabbani, Paul J Thornalley, Donald Smith, Allen Taylor; Glycemic Modulation of Age-related Macular Degeneration in Oxidatively-stressed Nrf2-null Mice. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2297.
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© ARVO (1962-2015); The Authors (2016-present)
Nrf2 is a transcription factor that coordinates an antioxidant response to diverse cellular stresses. Mice lacking Nrf2 (Nfe2l2) have increased oxidative stress and are reported to develop age-related retinopathy by 15 months. We sought to determine whether induction of additional glycemic stress would exacerbate retinopathy or conversely whether a low glycemia diet would be neuroprotective during aging. We also sought to determine whether these diets affected levels of advanced glycation end-products (AGEs).
3-month old Nrf2-null mice were pair fed high glycemia (HG) or low glycemia (LG) diets until mice were 18 months. Glycemic stress was determined by glucose tolerance test. Retina pathology was assessed via funduscopy, fluorescein angiography, histology, and electron microscopy. Glycative stress was assessed by measurement of AGEs from plasma and kidney tissue, using high-sensitivity stable isotopic dilution analysis LC-MS/MS.
Nrf2-null mice fed HG diets became overweight, hyperglycemic, and insulin resistant whereas those fed LG diets maintained normal weights and insulin sensitivity. Nrf2-null mice fed HG diets developed AMD-like features including photoreceptor degeneration, RPE atrophy and hypopigmentation, and accumulation of lipofuscin and phagosomes in the RPE. Some HG-fed mice showed vascular hemorrhages and choroidal neovascularization. In addition, large sub-RPE drusenoid deposits or edemas were observed. In contrast, LG-fed mice did not develop retinopathies and had normal appearing photoreceptors and RPE. Among AGEs, methyglyoxal-derived hydroimidazolone (MG-H1) was increased in the plasma of Nrf2-null mice relative to WT mice. Pentosidine and the AGE precursor fructosyl-lysine were increased in plasma and kidney tissue from HG-fed mice relative to LG-fed mice.
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. Loss of Nrf2 was associated with increased glycative stress, which could be partially ameliorated by consumption of a LG diet. Our studies point to the Nrf2-null mouse as an accelerated mouse model of AMD, and add to the accumulating evidence that healthy dietary patterns can be used to treat or prevent AMD.
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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