Optimization of a Retinal Pigment Epithelium Damage Model

Abstract

Purpose : Sodium iodate (NaIO₃) is selectively toxic to retinal pigment epithelium (RPE), inducing RPE cell death and subsequent photoreceptor degeneration. We sought to establish an NaIO₃-induced RPE damage model that exhibits repeatable, moderate functional and structural loss that would be useful for testing of potential therapies. We explored differences in NaIO₃-elicited responses of RPE and other retinal cells associated with mouse strain and dosing regimen.

Methods : Adult C57BL/6J mice and 129/SV-E mice were injected via tail vein with sodium iodate in PBS (0, 10, and 15mg/kg for 129/SV-E mice and 0, 10, 15, 20, 40mg/kg for C57BL/6J mice). Retinal function and structure were examined at 3 and 7 days post-injection by electroretinography (ERG), fundus photography, and optical coherence tomography (OCT). Post-mortem histology and immunohistochemical assessments were performed on retina sections and RPE flatmounts from subsets of cohorts.

Results : Tail vein injection of C57BL/6J mice with 15mg/kg NaIO₃ statistically significantly diminished scotopic a-, b-, and c-wave mean amplitudes within 3 days of injection (p<0.0001, n=7-8/group). Tail vein injection of 129/SV-E mice with 15mg/kg NaIO₃ statistically significantly diminished scotopic a- and b-wave (but not c-wave) mean amplitudes within 7 days of injection (p<0.01, n=3-4/group), but not at 3 days post-injection. OCT imaging revealed thinner retina thickness and blurred lines between each layer compared with the control group, differences that increased with increasing NaIO₃ concentration in injections. Fundus imaging revealed pale fundus with small white dots in NaIO₃-treated mice. Immunohistochemical staining of RPE flatmounts showed that NaIO₃ treatment caused central RPE damage, first evidenced by alpha-catenin membrane-to-cytosol translocation, followed by RPE sheet distortion, expanding to peripheral areas with increasing dosage concentration or with time post-injection. Doses greater than 15mg/kg NaIO₃ caused immediate and profound RPE damage and were not further explored.

Conclusions : The RPE toxicity of NaIO₃ delivered by tail vein injection increases with dose and with time following treatment. Low-dosage treatment produced relatively slowly-developing and repeatable RPE damage that may prove useful for testing therapeutic interventions.

This is a 2020 ARVO Annual Meeting abstract.