Abstract
Retinal vascular alterations represent an important but understudied form of microvascular target endorgan damage (TOD). To understand the pathomechanisms underlying hypertensive retinopathy, we used a double transgenic rat model (dTGR) established for TOD, which expresses both the rat and human RAS. Purpose of the study is to assess whether systemic hypertension affects retinal structure and function similar to the characteristic pathology in humans. We investigated the retinal phenotype by using immunohistochemistry of retinal whole mount preparations or sagittal sections, qPCR as well as functional analysis by Ganzfeld and pattern electro-retinography (ERG). Whole mount preparations revealed focal avascular areas, pathological vessels with irregularities in shape and diameter as well as neovascular tufts in dTGR rats compared to control animals. In sagittal sections we detected a loss of retinal ganglion cells. GFAP staining revealed activation of astrocytes in the ganglion cell layer (GCL) and astrocytosis of the optic nerve. VEGF-positive staining could be detected in the ganglion cell layer (GCL) and the inner nuclear layer (INL). To further substantiate the loss of ganglion cells detected in immunohistochemistry and to obtain a correlated functional analysis, pattern ERG were recorded. By using a stimulation with different pattern sizes (15° and 5-7°) at 2.4hz of the black and white checkerboard we showed that the positive component after about 50ms (P50) of the pattern ERG was significantly smaller in dTGR compared to control rats at 5-7° pattern size whereas the P50 at 15° remained unchanged. This indicates a loss of ganglion cells in the retina. qPCR revealed a non-detectable local renin expression, increase in MCP1 and sFLT1 expression and decrease in the expression of tight-junction proteins claudin-1 and occludin. Thus we present a first animal model for hypertensive retinopathy showing functional and structural alterations of the retina. Differential gene expression analysis suggests a strong local inflammatory response, loss of the blood/retina barrier and surprisingly low activity of the local renin-angiotensin-system. Further studies are warranted to investigate the local pathomechanisms.
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