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Krysten M Farjo, Laura Otalora, TJ Hollingsworth, Rafal Farjo, Alexander Quiambao; Over-expression of RBP4 Causes Progressive Retinal Degeneration in Mice. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3478.
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Elevated levels of serum retinol-binding protein (RBP4) contribute to the development of insulin resistance and type 2 diabetes. Moreover, patients with proliferative diabetic retinopathy have a significant increase in serum RBP4 levels compared to diabetic patients with mild or no retinopathy. We have previously shown that elevation of RBP4 induces inflammation in human retinal capillary endothelial cells by a retinol-independent mechanism, and thus may contribute to the formation of vascular lesions in diabetic retinopathy. The current study evaluates the physiologic effects of serum RBP4 elevation on the retina.
We are using transgenic mice that constitutively over-express RBP4 (RBP4-Tg), resulting in a ~10-fold increase in serum RBP4 levels compared to wild-type mice, which is similar to the level of RBP4 elevation in patients with long-duration type 2 diabetes. RBP4-Tg mice and wild-type controls were evaluated from 1 to 9 months of age to assess retinal function and structure by electroretinography (ERG) and histological analyses, respectively. To determine the effect of RBP4 elevation on retinal retinoid uptake and visual cycle activity, retinoid levels in mouse eyecups were quantified by high performance liquid chromatography.
The ERG scotopic a-wave amplitude is consistently diminished by ~33% in RBP4-Tg mice between ages 3-9 months, whereas the scotopic and photopic b-wave amplitudes are initially reduced by 20-30% at 3 months and progressively decline with age to a 50-70% reduction by 9 months of age. Quantitative “spidergram” histological analyses showed significant thinning of the outer and inner nuclear layers (ONL and INL) of the retina, with the INL thinning being more pronounced. This coincides with the dominant ERG b-wave reduction, as well as a significant increase in TUNEL-positive nuclei within the INL and increased expression of glial fibrillary acidic protein (GFAP), a marker of retinal gliosis. There was no difference in cumulative steady-state dark-adapted retinal retinoid profiles between RBP4-Tg and wild-type controls, indicating that the visual cycle is intact in RBP4-Tg mice. Further analyses of visual cycle kinetics and retinal inflammation are ongoing.
These results, in combination with our studies in human endothelium, suggest that elevation of serum RBP4 could contribute to both vascular lesions and neurodegeneration in diabetic retinopathy.
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