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Sarah B. Sunshine, Joel C. Sunshine, Marisol Cano, James T. Handa; The Role of Nitric Oxide in Dry and Wet Age-related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2012;53(14):3189.
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Age-related Macular Degeneration (AMD), the most common cause of blindness among the elderly in the US, has two forms. The "dry" form, characterized by retinal pigment epithelial (RPE) cell apoptosis and the "wet" form, characterized by pathologic angiogenesis. Nitric Oxide (NO) is a chief component of cigarette smoke (CS), the strongest risk factor for AMD. NO activates the cytoprotective transcription factor Nrf2. CS and NO induce RPE apoptosis, vascular permeability, and angiogenesis unless neutralized. NO from CS or neuronal nitric oxide synthase (nNOS), the predominant isoform in the RPE, could injure the RPE by impairing the Nrf2 response. We hypothesize that acute NO exposure induces the Nrf2 response whereas chronic NO causes Nrf2 failure, leading to dry AMD, and through NO’s pro-angiogenic properties, activate wet AMD.
NO was measured (DAF2DA) in ARPE19 cells treated with CS, SNAP (NO donor), or transfected with nNOS. The Nrf2 response was tested by measuring Nrf2 responsive gene (GCLM, NQO1, HO1) expression by RT-qPCR. Control and nNOS deficient mice were treated with NOS’s substrate, Arginine (70mg/ml), to increase NO, or water for 1-6 months. Laser induced rupture of Bruch’s membrane was used to generate choroidal neovascularization (CNV).
CS and nNOS transfected ARPE19 cells showed increased NO (10 and 2 fold) and increased expression of Nrf2 (1.6-fold p=0.05), GCLM (1.39-fold p=0.02), NQO1 (2.7-fold, p=0.005). Mice treated with arginine had increased expression of GCLM (2.13-fold, p=0.01), NQO1-(1.85-fold, p=0.04), HO1 (2.25-fold, p=0.03) at 6 months in the RPE, and no Nrf2 response in nNOS deficient mice. The area of CNV was paradoxically decreased by 41% (p=0.004) in arginine treated mice compared to controls.
Nrf2 protects the RPE from acute NO stress. NO from nNOS production likely mediated the Nrf2 response in the RPE of mice chronically exposed to arginine. A dramatic decrease in CNV size was observed in mice treated with arginine possibly through activated arginase. Further investigation of arginase is warranted as a potential new therapy for wet AMD.
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