RIP140-Mediated NF-κB Inflammatory Pathway Promotes Metabolic Dysregulation in Retinal Pigment Epithelium Cells

Abstract

Metabolic dysregulation of the retinal pigment epithelium (RPE) has been implicated in age-related macular degeneration (AMD). However, the molecular regulation of RPE metabolism remains unclear. RIP140 is known to affect oxidative metabolism and mitochondrial biogenesis by negatively controlling mitochondrial pathways regulated by PPAR-γ co-activator-1 α(PGC-1α). This study aims to disclose the effect of RIP140 on the RPE metabolic program in vitro and in vivo. RIP140 protein levels were assayed by Western blotting. Gene expression was tested using quantitative real-time PCR (qRT-PCR), ATP production, and glycogen concentration assays, and the release of inflammatory factors was analyzed by commercial kits. Mice photoreceptor function was measured by electroretinography (ERG). In ARPE-19 cells, RIP140 overexpression changed the expression of the key metabolic genes and lipid processing genes, inhibited mitochondrial ATP production, and enhanced glycogenesis. Moreover, RIP140 overexpression promoted the translocation of NF-κB and increased the expression and production of IL-1β, IL-6, and TNF-α in ARPE-19 cells. Importantly, we also observed the overexpression of RIP140 through adenovirus delivery in rat retinal cells, which significantly decreased the amplitude of the a-wave and b-wave measured by ERG assay. Therapeutic strategies that modulate the activity of RIP140 could have clinical utility for the treatment of AMD in terms of preventing RPE degeneration.