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Maria Constanza Paz, Pablo Barcelona, Paula Virginia Subirada Caldarone, Magali Evelin Ridano, Gustavo Alberto Chiabrando, Claudia Castro, Maria Cecilia Sanchez; Retinal dysfunction in early stages of Metabolic Syndrome established on a new experimental mouse model.. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2521.
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© ARVO (1962-2015); The Authors (2016-present)
Diabetic retinopathy (DR) is the most serious ocular complication associated with T2DM, which is a metabolic syndrome (MS), and one of the leading causes of blindness. Although animal models of DR have contributed to the knowledge of this disease, these models have some limitations in to reproduce completely the retinopathy. We proposed to analyze in early stages of the MS, markers of retinal vascular integrity and neuronal functionality.
We used C57BL/6 (WT) and Apolipoprotein E knockout (ApoE-KO) mice either fed with a normal diet (ND) or a 10% w/v fructose diet (FD) in drinking water from 2 months of age. Time-dependent kinetic studies were done from 4 to 6 months of age analyzing lipid profile, glucose tolerance test (GTT) and insulin tolerance test (ITT). For GTTs, WT or ApoE-KO with ND or FD-fed mice (n=8/group) were fasted 5 h prior to glucose injection (2g/kg, i.p.). For ITTs, mice (fasted 5 h) were injected with regular human insulin (0.75U/kg, i.p.). Blood samples were taken from the tail vein at time 0 (basal value) and at 0.5; 1 and 2 h after injections. Retinal functionality was assessed by ERG at 2, 3 and 4 month of treatment in mice dark-adapted (>15 hours). Retinal histology and immunofluorescence analysis were performed in flatmounts and cryosections, vascular permeability and leakage were quantified by Evans Blue extravasations. GraphPad Prism was employed for statistical analysis.
After 2 month of treatment, ApoE-KO FD showed dyslipidemic profile, altered GTT and ITT vs. other groups. At this time, the ERG a- and b- wave did not show changes but the oscillatory potential amplitudes were significantly decrease in retinas of these mice vs. ApoE-KO ND (p<0.05). In addition, ApoE-KO after 4 month of FD evidenced increased vascular permeability and leakage vs. ApoE-KO ND and WT ND or FD (p<0.05). At this early stage of the MS, the GFAP expression levels were observed just in astrocytes but not in Müller glial cells, demonstrating non-reactive gliosis in retinas of ApoE-KO FD.
The results showed that ApoE-KO after 2 months of FD presented metabolic alterations mimicking some features of human MS at its initial stages, accompanied by a partial retinal neuronal dysfunction that precedes the vascular changes. Thus, this model could offer the opportunity to investigate DR at an early stage of the MS, which shows increasing prevalence worldwide.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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