Neurotrophins enhance retinal pigment epithelial cell survival through neuroprotectin D1 signaling

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 104; no. 32; pp. 13152 - 13157
• Main Authors: Mukherjee, Pranab K, Marcheselli, Victor L, Barreiro, Sebastian, Hu, Jane, Bok, Dean, Bazan, Nicolas G
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 07.08.2007; National Acad Sciences
• Subjects: Apoptosis; Biological Sciences; Caspase 3 - metabolism; Cell culture techniques; Cell growth; Cell Survival - drug effects; Cells; Cells, Cultured; Cytoprotection; Docosahexaenoic Acids - metabolism; Docosahexaenoic Acids - pharmacology; Epithelial cells; Eye Proteins - pharmacology; Fatty acids; Humans; Lipids; Medicin och hälsovetenskap; Nerve Growth Factors - pharmacology; Neurons; Neuroprotective Agents - pharmacology; Neurosciences; Oxidative Stress; Photoreceptors; Pigment Epithelium of Eye - cytology; Pigment Epithelium of Eye - drug effects; Proteins; Pyridinium Compounds - toxicity; Retinal pigments; Retinoids - toxicity; Serpins - pharmacology; Signal transduction; Signal Transduction - physiology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0705949104

Integrity of retinal pigment epithelial cells is necessary for photoreceptor survival and vision. The essential omega-3 fatty acid, docosahexaenoic acid, attains its highest concentration in the human body in photoreceptors and is assumed to be a target for lipid peroxidation during cell damage. We have previously shown, in contrast, that docosahexaenoic acid is also the precursor of neuroprotectin D1 (NPD1), which now we demonstrate, acts against apoptosis mediated by A2E, a byproduct of phototransduction that becomes toxic when it accumulates in aging retinal pigment epithelial (RPE) cells and in some inherited retinal degenerations. Furthermore, we show that neurotrophins, particularly pigment epithelium-derived factor, induce NPD1 synthesis and its polarized apical secretion. Moreover, docosahexaenoic acid (DHA) elicits a concentration-dependent and selective potentiation of pigment epithelial-derived factor-stimulated NPD1 synthesis and release through the apical RPE cell surface. The bioactivity of signaling activated by pigment epithelium-derived factor and DHA uncovered synergistic cytoprotection with concomitant NPD1 synthesis when cells were challenged with oxidative stress. Also, DHA and pigment epithelium-derived factor synergistically modify the expression of Bcl-2 family members, activating antiapoptotic proteins and decreasing proapoptotic proteins, and by attenuating caspase 3 activation during oxidative stress. Thus, our findings demonstrate that DHA-derived NPD1 protects against RPE cell damage mediated by aging/disease-induced A2E accumulation. Also, our results identify neurotrophins as regulators of NPD1 and of its polarized apical efflux from RPE cells. Taken together, these findings imply NPD1 may elicit autocrine actions on RPE cells and paracrine bioactivity in cells located in the proximity of the interphotoreceptor matrix.