April 2014
Volume 55, Issue 13
ARVO Annual Meeting Abstract  |   April 2014
Peroxisome proliferator-activated receptor (PPAR) β/δ expression and activation in retinal pigment epithelial and choroidal endothelial cells: implication in age-related macular degeneration
Author Affiliations & Notes
  • Mayur Choudhary
    Opthalmology, Duke Eye Center, Durham, NC
  • Goldis Malek
    Opthalmology, Duke Eye Center, Durham, NC
  • Footnotes
    Commercial Relationships Mayur Choudhary, None; Goldis Malek, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science April 2014, Vol.55, 3438. doi:
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      Mayur Choudhary, Goldis Malek; Peroxisome proliferator-activated receptor (PPAR) β/δ expression and activation in retinal pigment epithelial and choroidal endothelial cells: implication in age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3438.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose: PPARs are members of a superfamily of nuclear receptors that play pivotal roles in the regulation of lipid homeostasis, energy metabolism, inflammation, extracellular matrix remodeling, cellular differentiation, proliferation and apoptosis, events also important in initiation and progression of age-related macular degeneration (AMD). Among the three isoforms identified, the physiological function of the PPARβ/δ [NR1C2] isoform, remains relatively unknown. It is expressed in a variety of cells and its activation has been postulated to exert anti-atherosclerotic effects by modulating lipoprotein metabolism and increasing the availability of inflammatory suppressors. Here, we investigated the expression and activity of the PPARβ/δ in retinal pigment epithelial (RPE) and choroidal endothelial cells, cells affected in AMD, and its effect on disease related pathogenic pathways.

Methods: PPARβ/δ expression and activity were determined in ARPE19 and RF/6A endothelial cells treated with synthetic agonists and antagonists of the receptor using qPCR, western blot and luciferase assays. Expression of inflammatory, extracellular matrix (ECM) molecules, and growth factors involved in fibrosis were measured in cells following knock-down of the receptor, and/or inflammatory stimulation and oxidative stress. RPE cells were also treated with native and oxidized lipids to validate them as endogenous ligands.

Results: The PPARβ/δ pathway is active in ARPE19 and RF/6A cells as shown by transcriptional activity assays and target gene expression in response to agonists. The induction of the PPAR reporter activity and target genes in response to dietary lipids confirmed their role as endogenous ligands. Agonist treatment caused an upregulation of TGFβ mRNA, and collagenIV and fibronectin secretion, which was inhibited by the antagonist. PPARβ/δ knockdown resulted in an increase in collagen1A1, IV, and vitronectin expression, underlining the involvement of the PPAR signaling pathway in ECM regulation.

Conclusions: Since homeostasis of the ECM and apoptosis of RPE and endothelial cells are potentially vital mechanisms in AMD pathogenesis and specifically deposit formation and fibrosis, our results support the hypothesis that the PPARβ/δ may be a regulatory signaling pathway in AMD. Further investigation is ongoing.

Keywords: 412 age-related macular degeneration • 519 extracellular matrix • 701 retinal pigment epithelium  

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