PPARβ/δ selectively regulates phenotypic features of age-related macular degeneration.
Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) is a nuclear receptor that regulates differentiation, inflammation, lipid metabolism, extracellular matrix remodeling, and angiogenesis in multiple tissues. These pathways are also central to the pathogenesis of age-related macular degeneration (AMD), the leading cause of vision loss globally. With the goal of identifying signaling pathways that may be important in the development of AMD, we investigated the impact of PPARβ/δ activation on ocular tissues affected in the disease. PPARβ/δ is expressed and can be activated in AMD vulnerable cells, including retinal pigment epithelial (RPE) and choroidal endothelial cells. Further, PPARβ/δ knockdown modulates AMD-related pathways selectively. Specifically, genetic ablation ofPparβ/δin aged mice resulted in exacerbation of several phenotypic features of early dry AMD, but attenuation of experimentally induced choroidal neovascular (CNV) lesions. Antagonizing PPARβ/δ in bothin vitroangiogenesis assays and in thein vivoexperimentally induced CNV model, inhibited angiogenesis and angiogenic pathways, while ligand activation of PPARβ/δ,in vitro, decreased RPE lipid accumulation, characteristic of dry AMD. This study demonstrates for the first time, selective regulation of a nuclear receptor in the eye and establishes that selective targeting of PPARβ/δ may be a suitable strategy for treatment of different clinical sub-types of AMD.
Department of Ophthalmology, Duke University School of Medicine, Durham, NC 27703, USA.
Mayur
M
Choudhary
Department of Ophthalmology, Duke University School of Medicine, Durham, NC 27703, USA.
Jin-Dong
JD
Ding
Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Xiaoping
X
Qi
Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Michael E
ME
Boulton
Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA.
Pei-Li
PL
Yao
Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA.
Jeffrey M
JM
Peters
Department of Ophthalmology, Duke University School of Medicine, Durham, NC 27703, USA.|Department of Pathology, Duke University School of Medicine, Durham, NC 27703, USA.
Goldis
G
Malek
D000368:Aged; D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004596:Electroretinography; D005260:Female; D006801:Humans; D008253:Macaca mulatta; D008268:Macular Degeneration / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D048068:PPAR-beta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013450:Sulfones / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D055815:Young Adult; D010636:Phenols; D013438:Sulfhydryl Compounds
D048068:PPAR-beta; D013450:Sulfones; D013844:Thiazoles; D013876:Thiophenes; C529769:GSK0660; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds
PPARβ/δ; age-related macular degeneration; angiogenesis; choroidal neovascularization; inflammation; nuclear receptors