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

Mayur Choudhary,Pei-Li Yao,Xiaoping Qi,Goldis Malek,Michael E Boulton,Jeffrey M Peters,Jin-Dong Ding

doi:10.18632/aging.101031

Abstract

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 of Pparβ/δ in 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 both in vitro angiogenesis assays and in the in vivo experimentally 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.

Highlights

Age-related macular degeneration (AMD) is the leading cause of vision loss in the elderly in the Western World
This short-term treatment with Peroxisome proliferator‐activated receptor‐β/δ (PPARβ/δ) agonist or antagonist, did not affect the integrity of the retinal pigment epithelial (RPE) tight junctions (Figure S10). These results are consistent with the in vitro studies and demonstrate that inhibition of PPARβ/δ activity results in a less severe choroidal neovascular (CNV) phenotype and may be beneficial in attenuating lesion formation in vivo. These studies demonstrate for the first time a role of PPARβ/δ in regulating different aspects of extracellular matrix turnover, angiogenesis, inflammation, and lipid processing in the eye
PPARβ/δ affects the RPE and choroidal endothelium differentially, selectively impacting the development of several fundamental AMD phenotypes. These data show that PPARβ/δ activity is functionally important in RPE and choroidal endothelial cell models systems; cells that are compromised during the initiation and progression of AMD

Summary

Introduction

Age-related macular degeneration (AMD) is the leading cause of vision loss in the elderly in the Western World. Advanced exudative or ‘wet’ AMD is characterized by endothelial invasion www.aging‐us.com through Bruch’s membrane and pathological growth of abnormal new vessels originating from the choroid, below the RPE, resulting in the formation of choroidal neovascular (CNV) lesions, which are responsible for the most severe form of disease-related vision loss [1, 3, 12] Both the increase in life expectancy of the general population, and prevalence of AMD in the elderly population with age [2, 3], ensures that this disease will become an even greater health problem in the near future. This leaves more than 30% of the patient population, for which an alternative treatment must be found

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Conclusion