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Mayur Choudhary, Lincoln V Johnson, David Forest, Xiaoping Qi, Michael E Boulton, Goldis Malek; Targeting the peroxisome proliferator-activated receptor β/δ (PPARβ/δ): Implications for dry and wet age-related macular degeneration (AMD). Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4213.
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The early dry and late wet forms of AMD are characterized by accumulation of deposits below the retinal pigment epithelium (RPE) and choroidal neovascularization (CNV), respectively, leading to vision loss in the elderly. Previously we found that the nuclear receptor PPARβ/δ is active in cells vulnerable in AMD, including RPE and choroidal endothelial cells (EC), where it can regulate genes involved in lipid homeostasis, inflammation, extracellular matrix remodeling, endoplasmic reticulum (ER) stress, and angiogenesis events which contribute to AMD development. Here we investigated the consequences of targeting PPARβ/δ activity, on pathologies associated with AMD.
ARPE19 (human RPE cells) and RF6A (macaque choroidal EC) cultures were treated with pharmacological (GW0742) and endogenous agonists (lipids), and an antagonist (GSK0660) of PPARβ/δ. C/EBP homologous protein (CHOP) expression was used as a marker of ER stress. Phenotypic characteristics of dry and wet AMD were studied in in vitro models of, sub-RPE ‘drusenoid’ deposit formation, using differentiated fetal RPE (fRPE) cells cultured for up to 3 months, and angiogenesis/wound healing, using basic fibroblast growth factor (bFGF)-induced tube-formation/migration of RF6A cells. Retinal morphology and lipofuscin autofluorescence were evaluated in cryosections of aged Pparβ/δ-/- and Pparβ/δ+/+ mouse eyes. The effect of receptor expression and function on lesion formation was measured following laser induced CNV.
In RPE cells, treatment with lipids and hydroquinone resulted in ER stress, which was rescued by GSK0660. In RF6A, GSK0660 inhibited bFGF-induced migration (58%) and tube-formation (61%), while GW0742 suppressed bFGF-induced proliferation (29%). Though the overall morphology of Pparβ/δ-/- mouse retinas appeared normal with pockets of very thin continuous sub-RPE basal laminar-like deposits, most likely associated with aging, the Pparβ/δ-/- RPE cells displayed significantly higher autofluorescence compared to wild-type mice. We have also evaluated the effect of PPARβ/δ drugs on deposit formation in the fRPE model.
The data support the hypothesis that PPARβ/δ may be a regulatory signaling pathway in AMD and that its inhibition may be therapeutically beneficial in ameliorating pathologies associated with the disease.
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