Retinal Degeneration in a Klotho-overexpressing Mouse

Abstract

The klotho-overexpressing mouse, EFmKL46, is an animal model of insulin resistance that is not hyperglycemic. In this study, the retinopathy associated with altered insulin signaling in this transgenic animal is evaluated. In four young (8-16 weeks) and 12 aged (70-80 weeks) EFmKL46 mice and age/ sex matched wild type controls, the retinal vasculature was visualized by fluorescence angiography and fundus photography. Photoreceptor function was evaluated by electroretinography (ERG). Tissue sections from post-mortem retinas were histologically examined for retinal layer anomalies and degeneration. Immunohistochemisty was used to visualize the klotho protein in mouse retinas and human retinal pigment epithelium (RPE) cells. Aged EFmKL46 mice had abnormal retinal vasculature including tortuous veins, hemorrhages, and microaneurysms. Hypo/hyperpigmentation of the retina and possible retinal scarring and exudates were observed. ERG analysis showed decreased a/b-wave amplitudes. Histological examination showed a wavy photoreceptor-RPE interface and photoreceptor degeneration which ranged from outer segment loss to the complete deterioration of the photoreceptor layer. In aged EFmKL46 mice with complete photoreceptor loss, the RPE was thickened and showed areas of proliferation. Outer retinal layers were destroyed. Antibodies indicated klotho was present throughout the retina and human RPE cells. No retinal anomalies were observed in young EFmKL46 and young and aged wild type mice. In conclusion, the nonhyperglycemic, klotho-overexpressing mouse has retinal pathologies consistent with those seen in other animal models of insulin-dependent and insulin-resistant diabetes and is a promising tool for more detailed studies of pathologies associated with insulin signaling dysfunction.