CD36 ligand MPE-001 protects retinal pigment epithelial cells from oxidative stress via autophagy activation

Oxidative damage to the retinal pigment epithelium (RPE) is a key factor in the progression of age-related macular degeneration (AMD), a leading cause of vision loss. Current treatments for AMD often target late-stage neovascularization, but effective strategies to protect RPE cells from early oxidative stress are lacking. Ligands of cluster of differentiation 36 (CD36) have previously shown promise in preserving photoreceptor integrity in animal models of AMD, but the underlying cytoprotective mechanisms in RPE cells remained unclear. This study investigates how a specific CD36 ligand, MPE-001, exerts its protective effects.

Researchers investigated the cytoprotective effects of the CD36 ligand MPE-001 on human RPE cells subjected to oxidative stress. Oxidative damage was induced using sodium iodate (NaIO3), which triggers the formation of reactive oxygen species and apoptosis. The study assessed the impact of MPE-001 on reactive oxygen species levels and apoptosis. They employed immunoblotting and immunostaining assays to evaluate changes in autophagic flux and the formation of mature autophagosomes. To confirm the role of autophagy, experiments were repeated in the presence of autophagy inhibitors wortmannin and bafilomycin A1.

MPE-001 significantly reduced NaIO3-induced formation of reactive oxygen species and subsequent apoptosis in human RPE cells. This protective effect occurred independently of changes in antioxidant enzyme transcription. The study revealed that MPE-001 restored the autophagic flux that was disrupted by NaIO3. This restoration was specifically associated with an increase in syntaxin 17-positive mature autophagosomes, indicating enhanced autophagosome maturation. The critical role of autophagy in MPE-001's cytoprotective action was definitively demonstrated:

The protective effect of MPE-001 was completely abolished when autophagy inhibitors wortmannin and bafilomycin A1 were co-administered, confirming an autophagy-dependent mechanism.