Protective Effect of Met12, a Small Peptide Inhibitor of Fas, on the Retinal Pigment Epithelium and Photoreceptor After Sodium Iodate Injury

PURPOSE: A major problem in macular degeneration is the inability to reduce RPE and photoreceptor death. These cells die by necroptosis and apoptosis, respectively, but the upstream activator(s) of these death pathways is unknown. In this study, we use the sodium iodate (NaIO3) model of oxidative stress to test the hypothesis that activation of the Fas receptor contributes to the death of the RPE and photoreceptors. METHODS: Sodium iodate was injected in Brown-Norway rats via femoral vein injection. Both in vivo (fundus photography, optical coherence tomography, and fluorescein angiography) and ex vivo (histology, immunohistochemistry, Western blot, and RT-PCR) analyses of the RPE and retina were conducted at baseline, as well as at various times post NaIO3 injection. The ability of intravitreal injection of Met12, a small peptide inhibitor of the Fas receptor, to prevent RPE and photoreceptor cell death was assessed. RESULTS: Injection of NaIO3 led to Fas-mediated activation of both necroptosis and apoptosis in the RPE and photoreceptors, respectively. This was accompanied by a significant increase in the number of microglia/macrophages in the outer retina. Met12 significantly reduced the activation of the Fas-mediated death pathways, resulting in reduced RPE and photoreceptor death and a decreased immune response. CONCLUSIONS: Our results demonstrate that NaIO3 activates Fas-mediated cell death, both in the RPE and photoreceptor, and that a small peptide antagonist of the Fas receptor, Met12, significantly reduces the extent of this cell death. These findings suggest a role for Fas inhibition to protect the RPE and photoreceptors from death due to oxidative stress.