PPARβ/δ selectively regulates phenotypic features of age-related macular degeneration

Peroxisome proliferator-activated receptor-beta/delta (PPAR beta/delta) 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 beta/delta activation on ocular tissues affected in the disease. PPAR beta/delta is expressed and can be activated in AMD vulnerable cells, including retinal pigment epithelial (RPE) and choroidal endothelial cells. Further, PPAR beta/delta knockdown modulates AMD-related pathways selectively. Specifically, genetic ablation of Ppar beta/delta 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 beta/delta 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 beta/delta, 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 beta/delta may be a suitable strategy for treatment of different clinical sub-types of AMD.