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Krysten M Farjo, Laura Otalora, Mei Du, Ashley Martin, Gennadiy P Moiseyev, Phillip Vanlandingham, Rafal Farjo, Alexander Quiambao; Transgenic Mice Over-Expressing Serum Retinol-Binding Protein have Progressive Inner Retinal Degeneration Caused by a Retinoid-Independent Mechanism. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5425.
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© ARVO (1962-2015); The Authors (2016-present)
Serum retinol-binding protein (RBP4) is the transport protein for retinol (Vitamin A) in the blood. We and others have previously shown that RBP4 is also an adipokine with retinoid-independent pro-inflammatory activity, and RBP4 elevation in serum has been linked to cardiovascular diseases, insulin resistance, type 2 diabetes, and diabetic retinopathy. Here we evaluate the physiological, structural, and biochemical effects of serum RBP4 elevation on the retina.
RBP4-transgenic (RBP4-Tg) mice constitutively over-express RBP4, resulting in a ~10-fold increase in serum RBP4 levels compared to wild-type (WT) mice. RBP4-Tg and WT controls were evaluated from 1-9 months of age by optokinetic tracking (OKT), electroretinography (ERG), quantitative "spidergram" histological analyses, and immunohistochemical staining of the retina. Retinoid and bis-retinoid A2E levels were quantified in mouse eyecups by high performance liquid chromatography.
The OKT contrast threshold in RBP4-Tg mice was reduced by 25% at 1-month and 53% at 6-months of age, whereas OKT spatial frequency was reduced by 15% at 6-months of age. The RBP4-Tg ERG scotopic and photopic b-wave amplitudes were both significantly decreased by 1-month of age (~20% reduction), and progressively declined with aging (~60-75% reduction). In contrast, the RBP4-Tg ERG scotopic a-wave amplitude remained unchanged until 6-months of age (25% reduction). RBP4-Tg mice have a subtle yet significant thinning of the outer and inner nuclear layers (ONL and INL) of the retina, with the INL thinning being more pronounced and coinciding with the dominant ERG b-wave amplitude reduction phenotype. As early as 1-month of age, RBP4-Tg mice have GFAP expression in Muller cells, retinal microglia activation, and degradation of photoreceptor ribbon synapses, and by 6-months of age there is decreased bipolar cell density in the central retina. There was no difference in cumulative steady-state dark-adapted retinal retinoid profiles or bis-retinoid A2E levels between RBP4-Tg and wild-type controls, indicating that RBP4-Tg mice have normal retinoid visual cycle activity.
Elevated levels of serum RBP4 can impair retinal synaptic connectivity and promote inner retinal dysfunction and progressive retinal degeneration by a retinoid-independent mechanism.
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