Electrophysiologic and Morphologic Strain Differences in a Low-Dose NaIO₃-Induced Retinal Pigment Epithelium Damage Model

Abstract

We aimed to explore differences in the NaIO 3 -elicited responses of retinal pigment epithelium (RPE) and other retinal cells associated with mouse strains and dosing regimens.Methods: One dose of NaIO 3 at 10 or 15 mg/kg was given intravenously to adult male C57BL/6J and 129/SV-E mice. Control animals were injected with PBS. Morphologic and functional changes were characterized by spectral domain optical coherence tomography, electroretinography, histologic, and immunofluorescence techniques.Results: Injection with 10 mg/kg of NaIO 3 did not cause consistent RPE or retinal changes in either strain. Administration of 15 mg/kg of NaIO 3 initially induced a large transient increase in scotopic electroretinography a-, b-, and c-wave amplitudes within 12 hours of injection, followed by progressive structural and functional degradation at 3 days after injection in C57BL/6J mice and at 1 week after injection in 129/SV-E mice. RPE cell loss occurred in a large posterior-central lesion with a ring-like transition zone of abnormally shaped cells starting 12 hours after NaIO 3 treatment.Conclusions: NaIO 3 effects depended on the timing, dosage, and mouse strain. The RPE in the periphery was spared from damage compared with the central RPE. The large transient increase in the electroretinography was remarkable.Translational Relevance: This study is a phase T1 translational research study focusing on the development and validation of a mouse model of RPE damage. It provides a detailed foundation for future research, informing choices of mouse strain, dosage, and time points to establish NaIO 3 -induced RPE damage.

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

“…As previously reported [ 24 , 25 ], we also confirmed that RPE damage resulting from NaIO 3 -induced oxidative stress in mice could be divided into three regions with distinct RPE morphologies, i.e., normal-appearing RPE (“normal RPE”) (periphery), elongated RPE (transitional zone), and severely damaged or lost RPE (center) ( Figure 1 ), which seemed to reflect the degrees of RPE damage. Indeed, we observed that the degree of retinal photoreceptor cell death was correlated with these three regions.…”

“…These are the periphery with normal hexagonal cells that have a cobblestone-like appearance, the transitional zone with elongated and enlarged cells that still have ZO-1 at cell junctions, and the center with severely damaged cells that are unrecognizable or lost. Similar observations have been described with NaIO 3 -induced RPE damage in several reports, and therefore these features seem common morphological changes caused by NaIO 3 [ 24 , 25 , 53 ]. It should be noted that although we call morphologically normal-appearing RPE as “normal RPE”, normal ZO-1 staining patterns do not indicate that the RPE is physiologically and functionally normal.…”

“…Oxidative stress plays an important role in both physiology and diseases of the RPE. To study retinal degeneration, NaIO 3 , an oxidizing agent that is exclusively toxic to the RPE, has long been used as an oxidative stress model in vivo in various mammalian species [ 12 , 13 , 14 , 17 , 21 , 24 , 25 , 43 , 52 ]. However, since most of the earlier studies were conducted with a focus on retinal degeneration by using a high dose of NaIO 3 , understanding of the detailed nature of RPE damage itself with a low dose of NaIO 3 is still limited [ 25 ].…”

“…To study retinal degeneration, NaIO 3 , an oxidizing agent that is exclusively toxic to the RPE, has long been used as an oxidative stress model in vivo in various mammalian species [ 12 , 13 , 14 , 17 , 21 , 24 , 25 , 43 , 52 ]. However, since most of the earlier studies were conducted with a focus on retinal degeneration by using a high dose of NaIO 3 , understanding of the detailed nature of RPE damage itself with a low dose of NaIO 3 is still limited [ 25 ]. To better understand the NaIO 3 model in mice, we optimized the dose of NaIO 3 and further refined a morphometric method to quantify RPE damage caused by NaIO 3 -induced oxidative stress.…”

“…In our hands, NaIO 3 at 20 mg/kg BW resulted in a nearly complete RPE loss in male C57BL/6J mice. Recently, to refine the NaIO 3 -induced RPE damage model, the effects of NaIO 3 were analyzed in detail with respect to mouse strain, dosage, and time points, and 15 mg/kg BW was the lowest dose to induce reproducible RPE damage with the three distinct regions, i.e., periphery, transitional zone, and center [ 25 ]. With NaIO 3 at 15 mg/kg BW, we also observed the three regions similar to those reported.…”