Fine Tuning of an Oxidative Stress Model with Sodium Iodate Revealed Protective Effect of NF-κB Inhibition and Sex-Specific Difference in Susceptibility of the Retinal Pigment Epithelium.

Oxidative stress of the retinal pigment epithelium (RPE) is a major risk factor for age-related macular degeneration (AMD). As a dry AMD model via oxidative stress, sodium iodate (NaIO 3 ), which is primarily toxic to the RPE, has often been used at a high dose to cause RPE death for studying photoreceptor degeneration. Thus, characterization of RPE damage by a low dose of NaIO 3 is still limited. To quantify RPE damage caused by NaIO 3 in mice, we recently developed a morphometric method using RPE flat-mounts. Here, we report that NaIO 3 has a narrow range of dose-effect correlation at 11-18 mg/kg body weight in male C57BL/6J mice. We evaluated the usefulness of our quantification method in two experimental settings. First, we tested the effect of NF-κB inhibition on NaIO 3 -induced RPE damage in male C57BL/6J mice. IKKβ inhibitor BAY 651942 suppressed upregulation of NF-κB targets and protected the RPE from oxidative stress. Second, we tested sex-specific differences in NaIO 3 -induced RPE damage in C57BL/6J mice using a low dose near the threshold. NaIO 3 caused more severe RPE damage in female mice than in male mice. These results demonstrate the usefulness of the quantification method and the importance of fine-tuning of the NaIO 3 dose. The results also show the therapeutic potential of IKKβ inhibition for oxidative stress-related RPE diseases, and reveal previously-unrecognized sex-specific differences in RPE susceptibility to oxidative stress.