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A. A. Herzlich, X. Ding, D. Shen, R. Ross, J. Tuo, C. C. Chan; Peroxisome Proliferator Activated Receptors (PPARs) in AMD-Like Lesions in Eyes of Ccl2-/-Cx3cr1-/-Mice. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5413.
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Peroxisome proliferator-activated receptors (PPARs) play an important role in lipid degeneration, immune regulation, oxidative stress, vascular endothelial growth factor (VEGF) regulation and docosahexaenoic acid(DHA) turnover, which are implicated in the pathophysiology of age-related macular degeneration (AMD). PPAR γ is known to be expressed in retinal pigment epithelium (RPE), an essential cell in photoreceptor regeneration and vision maintenance. In order to solidify the relationship between PPAR and AMD, we examined PPAR expression in Ccl2-/-/Cx3cr1-/- mice, who develop pathological changes resembling human AMD.
PPAR α, β, and γ protein expression in retina of wild type and 3 different groups of Ccl2-/-/Cx3cr1-/- mice was determined by avidin-biotin complex immunoperoxidase technique. The groups of Ccl2-/-/Cx3cr1-/- were fed a normal diet, a diet high in omega-3 fatty acids (rich in DHA), and a diet low in omega-3, respectively. Human retinal expression of PPAR γ was also tested. PPAR γ and VEGF transcript expression in mice eyes was determined in wild type and Ccl2-/-/Cx3cr1-/- mice using Taqman probes.
PPAR α, β, and γ proteins are diffusely expressed in the neuroretina and RPE in mouse and human. The sequence of PPAR γ protein expression from highest to lowest is: Ccl2-/-/Cx3cr1-/- mice on a low omega-3 diet, Ccl2-/-/Cx3cr1-/- mice on a normal diet, Ccl2-/-/Cx3cr1-/- mice on a high omega-3 diet, and wild type mice. PPAR α and β transcripts are expressed equally in all groups. PPAR γ mRNA expression is 2.79 fold higher in Ccl2-/-/Cx3cr1-/- mice as compared to wild type. VEGF mRNA expression is 3.02 fold higher in Ccl2-/-/Cx3cr1-/- mice than in wild type.
PPAR α, β, and γ is present in neuroretinal and RPE cells. PPAR γ transcript and protein expression is higher in Ccl2-/-/Cx3cr1-/- mice as compared to wild type, which suggest a role for oxidative stress in the AMD-like phenotype. PPAR γ protein expression in Ccl2-/-/Cx3cr1-/- mice fed a high omega-3 diet is similar to wild type mice, whereas Ccl2-/-/Cx3cr1-/- mice fed a low omega-3 diet show levels comparable to Ccl2-/-/Cx3cr1-/- mice on a normal diet. The data suggest that a diet high in omega-3 may protect retinal integrity. Also, elevated VEGF transcripts in Ccl2-/-/Cx3cr1-/- mice as compared to wild type may be associated with aberrant PPAR γ expression in the retina of the Ccl2-/-/Cx3cr1-/- mice.
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