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Yun-Zheng Le, Yan Liu, Meili Zhu, Huizhuo Xu; Imaging Diabetes-induced Outer Blood-retina Breakdown: Implications in Diagnosis and Treatment of Diabetic Macular Edema. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3559.
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To investigate the significance of diabetes-induced RPE barrier breakdown, we established an imaging assay and examined the RPE barrier-specific leakage of macromolecules under ischemic and diabetic conditions. Using this assay, we also explored the therapeutic potential of treating RPE barrier breakdown in various rodent models.
Diabetic and ischemic rodents were injected intravenously with fluorescent macromolecules. The RPE barrier-specific leakage in diabetic and ischemic rodents was visualized and quantified by fluorescent microscopy. This imaging assay was also used to determine the effect of inhibiting diabetes- or ischemia-induced RPE barrier breakdown in mouse models of conditional gene knockout or biochemical inhibition.
A microscopic imaging assay was developed to examine diabetes- or ischemia-induced RPE barrier breakdown specifically. Substantial leakages of macromolecules through the RPE barrier in diabetic and ischemic rodents were detected with this assay. The number of severe breaking points is inversely proportional to the size of macromolecules. The RPE barrier-specific leakage of macromolecules was significantly reduced in mouse model of RPE-specific knockout of vascular endothelial growth factor (VEGF) or its receptor (VEGF-R2) and in mouse model of biochemical inhibition of extracellular-signal-regulated kinase (ERK) signaling.
For the first time, a microscopic imaging assay for visualizing and quantifying RPE barrier-specific leakage of macromolecules in diabetic and ischemic rodents was developed. Our results suggest that the breakdown of the RPE barrier contributes significantly to overall blood-content leakage under diabetic and ischemic conditions, which is regulated through an autocrine VEGF signaling mechanism. The breakdown of the RPE barrier under these pathological conditions can be treated with genetic and biochemical alternations. Therefore, our study may have significant implications to the mechanism and diagnosis of diabetic retinopathy. In addition, our imaging assay is an excellent tool to screen drugs for the treatment of diabetic macular edema.
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