PP2A and LRP‐1 targeted protection of human retinal pigment epithelial cells

Abstract

Retinal pigment epithelial (RPE) cell disorders contribute to the leading causes of vision loss in the United States. Diabetic retinopathy and Age‐related macular degeneration are RPE disorders that develop as a consequence to the accumulation of toxic retinal lipids. However, the mechanism of how RPE regulates lipid homeostasis in response to intra‐retinal dysfunction of lipid metabolism is unknown. The purpose of this project is to provide new proof of principle information, toward the understanding, of how RPE regulates oxidative stress induced alteration of intracellular phosphatase/kinase signaling leading to retinal disorders. Through confocal immunofluorescence imaging, transepithelial resistance (TEER) measurement and Western Blot analysis of protein expression of primary human RPE(hRPE) cells are investigated after the treatment of lipid peroxidation products. Protein phosphatase 2A (PP2A), appears to have a pertinent role in the regulation of kinases (p‐Akt and p‐ERK ½) associated to RPE loss and TEER maintenance in response to oxidative stress induced by lipid peroxidation products. Altered PP2A signaling was found to be modulated by low density lipoprotein related receptor protein‐1 (LRP‐1) targeted peptidomimetic treatment. This project also provides potential clinical application to the treatment of retinal degeneration associated with intraretinal lipid homeostasis using a patented peptidomimetic targeting LRP‐1 and PP2A signaling.