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

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.

Investigating the Role of PPARβ/δ in Retinal Vascular Remodeling Using Pparβ/δ-Deficient Mice

“…Genetic disruption of Pparβ / δ and specific PPARβ/δ antagonists have previously been shown to attenuate laser-induced CNV in mice [ 21 ]. Surprisingly, our study showed no detectable PPARβ/δ protein in the choroid/retinal pigment epithelium (RPE) fraction of C57BL/6 mouse eyes ( Figure 1 a).…”

“…A previous study reported a reduced lesion size in Pparβ/δ −/− mice subjected to laser-induced CNV [ 21 ]. Surprisingly, our study could not detect PPARβ/δ in the RPE/choroid fraction of C57BL/6 mouse eyes.…”

A2E induces the transactivation of RARs, PPARs and RXRs and its effects are counteracted by norbixin in retinal pigment epithelium cellsin vitro

“…PPAR-b/d modulation seems to play different roles in dry AMD and neovascular AMD models. Pharmacological inhibition of PPAR-b/d signalling in vitro on RPE cells or in vivo in the mouse laser-induced choroidal neovascularization model, limited angiogenesis (54), but exacerbated signs of dry AMD. Conversely, activation of PPAR-b/d reduced lipid accumulation in RPE cells in vitro (a symptom in intermediate dry AMD) [55].…”

Effect of Anti-C5a Therapy in a Murine Model of Early/Intermediate Dry Age-Related Macular Degeneration

“…RNA from ARPE-19 cells was generously provided by Goldis Malek (Duke University) and was isolated as previously described. 36 RNA (150 ng) from each sample was used to synthesize cDNA using ProtoScript II Reverse Transcriptase (NEB, Ipswich, MA, USA). Each RT-PCR reaction contained 7.5 ng cDNA, 200 nmol/L each primer, and 12.5 μL iQ SYBR green supermix (Bio-Rad) in 25 μL total volume.…”