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 agerelated macular degeneration (AMD). As a dry AMD model via oxidative stress, sodium iodate (NaIO₃ ), 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 NaIO₃ is still limited. To quantify RPE damage caused by NaIO₃ in mice, we recently developed a morphometric method using RPE flat-mounts. Here, we report that NaIO₃ 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 NaIO₃-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 NaIO₃-induced RPE damage in C57BL/6J mice using a low dose near the threshold. NaIO₃ 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 NaIO₃ 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.