Oxidative Stress and Lipid Accumulation Augments Cell Death in LDLR-Deficient RPE Cells and Ldlr -/- Mice

• Published in: Cells (Basel, Switzerland) Vol. 12; no. 1; p. 43
• Main Authors: Sreekumar, Parameswaran Gangadharan, Su, Feng, Spee, Christine, Araujo, Eduardo, Nusinowitz, Steven, Reddy, Srinivasa T, Kannan, Ram
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 22.12.2022; MDPI
• Subjects: Age; Animals; Apoptosis; Atherosclerosis; Butyl hydroperoxide; Caspase 3 - metabolism; Caspase-3; Cell culture; Cell Death; Cholesterol; Cornea; Electroretinograms; geographic atrophy; Humans; inflammation; Laboratories; Lipid peroxidation; Lipids; Lipoproteins; Localization; Low density lipoprotein; Low density lipoprotein receptors; low-density lipoprotein receptor; Macular degeneration; Macular Degeneration - metabolism; Medical research; Mice; Mueller cells; Oxidative stress; Oxidative Stress - physiology; Receptors, LDL - genetics; Receptors, LDL - metabolism; Retina; retinal degeneration; retinal pigment epithelium; Tomography; Los Angeles California; United States > US; retinal degeneration; geographic atrophy; low-density lipoprotein receptor; inflammation; retinal pigment epithelium; oxidative stress; retinal function
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells12010043

Lipid peroxidation from oxidative stress is considered a major contributor to age-related macular degeneration (AMD). The retina is abundant with circulating low-density lipoproteins (LDL), which are taken up by LDL receptor (LDLR) in the RPE and Müller cells. The purpose of this study is to investigate the role of LDLR in the NaIO -induced model of dry AMD. Confluent primary human RPE (hRPE) and LDLR-silenced ARPE-19 cells were stressed with 150 µM tert-butyl hydroperoxide (tBH) and caspase 3/7 activation was determined. WT and mice were administered NaIO (20 mg/kg) intravenously. On day 7, fundus imaging, OCT, ERG, and retinal thickness were measured. Histology, TUNEL, cleaved caspase 3 and lipid accumulation were assessed. Treatment of hRPE with tBH markedly decreased LDLR expression. Caspase 3/7 activation was significantly increased in LDLR-silenced ARPE-19 cells treated with tBH. In mice, NaIO administration resulted in significant (a) retinal thinning, (b) compromised photoreceptor function, (c) increased percentage of cleaved caspase 3 positive and apoptotic cells, and (d) increased lipid droplet accumulation in the RPE, Bruch membrane, choroid, and sclera, compared to WT mice. Our findings imply that LDLR loss leads to lipid accumulation and impaired retinal function, which may contribute to the development of AMD.