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Nan Zhang, Xian Zhang, Preston Girardot, Vivian Summers, Jana T Sellers, Ying Li, Micah A Chrenek, John M Nickerson, Jeffrey H Boatright; Optimization of a Retinal Pigment Epithelium Damage Model. Invest. Ophthalmol. Vis. Sci. 2020;61(7):4441.
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© ARVO (1962-2015); The Authors (2016-present)
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.
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.
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.
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.
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