PPAR?/? selectively regulates phenotypic features of age-related macular degeneration.

ABSTRACT: Peroxisome proliferator-activated receptor-?/? (PPAR?/?) 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 PPAR?/? activation on ocular tissues affected in the disease. PPAR?/? is expressed and can be activated in AMD vulnerable cells, including retinal pigment epithelial (RPE) and choroidal endothelial cells. Further, PPAR?/? knockdown modulates AMD-related pathways selectively. Specifically, genetic ablation of Ppar?/? in aged mice resulted in exacerbation of several phenotypic features of early dry AMD, but attenuation of experimentally induced choroidal neovascular (CNV) lesions. Antagonizing PPAR?/? in both in vitro angiogenesis assays and in the in vivo experimentally induced CNV model, inhibited angiogenesis and angiogenic pathways, while ligand activation of PPAR?/?, 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 PPAR?/? may be a suitable strategy for treatment of different clinical sub-types of AMD.

SUBMITTER: Choudhary M 

PROVIDER: S-EPMC5076447 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature