Purchase this article with an account.
Rithwick Rajagopal, Emily Siebert, Sheng Zhang, Clay Semenkovich; Identification of Novel Peroxisome Proliferator-Activated Receptor Alpha Transcriptional Targets in the Retina. Invest. Ophthalmol. Vis. Sci. 2016;57(12):5435.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
The peroxisome proliferator-activated receptor alpha agonist fenofibrate prevents progression of diabetic retinopathy, yet its mechanism of protective action is not known. Here, we tested the hypothesis that peroxisome proliferator-activated receptor alpha agonists promote retinal health in the setting of diabetes by inducing a unique transcriptional signature in the eye.
First, we induced peroxisome proliferator-activated receptor alpha activity in the retina using systemically- or locally-introduced agonists and measured changes in canonical transcriptional targets. Second, we investigated retinal peroxisome proliferator-activated receptor responsiveness using a transgenic reporter system. Third, we performed a microarray analysis of transcript changes in whole retina after intravitreous delivery of several peroxisome proliferator-activated receptor alpha agonists and validated putative targets.
Canonical genes involved in lipid metabolism and beta-oxidation are not upregulated in the retina following systemic or local administration of peroxisome proliferator-activated receptor alpha agonists. However, these drugs can induce peroxisome proliferator-responsive element-dependent transcriptional activity when delivered locally, but not systemically, as assessed by reporter gene activity. A microarray analysis of gene expression after local peroxisome proliferator-activated receptor alpha agonism revealed several potential transcriptional targets in the retina. Two candidate genes, one encoding a 250 kDa membrane-associated actin-binding protein and the other encoding a 28 kDa cell surface glycoprotein, were validated by quantitative polymerase chain reaction and western blotting.
Although peroxisome proliferator-activated receptor alpha coordinates transcription of genes involved in lipid metabolism in most tissues, it does not appear to do so in the retina. Yet, the retina does possess local peroxisome proliferator responsiveness. Our results suggest that a retina-specific transcriptional profile may account for the ameliorative actions of peroxisome proliferator-activated receptor alpha within the diseased retina.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
This PDF is available to Subscribers Only