Retinal gene profiling in a hereditary rodent model of elevatedintraocular pressure

[摘要] Purpose: To characterize the changes in retinal gene expressioninduced by elevated intraocular pressure (IOP) in a hereditary rodentmodel.Methods: A rat model derived from the RCS-rdy- strain developsIOP elevation spontaneously without experimental manipulation. Retinalgene expression after IOP elevation was compared with age-matchedRCS-rdy- retinas having normal IOP levels The MWG Rat 10k array,which comprises 9715 rat genes spotted onto one array was used.Quantitative real-time PCR (qRT-PCR) was used to verify the expressionof heat shock protein-27 (Hsp-27), SA hypertension-associated gene,c-myc, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), vascularendothelial growth factor (VEGF), myocilin, interleukin-7 (IL-7),mitogen activated protein kinase 13 (MAPK-13) and crystallin beta-A1(Cryba1). The cellular distribution of c-myc, glial fibrillary acidicprotein (GFAP), VEGF, and SA was assessed using immunohistochemistry.Results: Elevated IOP of 37.7±5.0 mmHg shifted the retina'sprogram of gene expression, with 75 genes being upregulated (equal to orhigher than 3.0 fold) and 45 genes being downregulated (equal to orlower than 0.3 fold). These genes mediate various cellular processessuch as cell adhesion, cell structure, hypertension, immunity, proteinsythesis, proteolysis, transcription, and signaling. The regulationpattern of SA, VEGF, c-myc, IL-7, and MAPK-13, which are uniquelyregulated in our model were confirmed by qRT-PCR experiments. Theregulation of Hsp-27, TIMP-1, myocilin, and Cryba1, which havepreviously been associated with elevated IOP were also confirmed withqRT-PCR. The protein products of c-myc, SA, and GFAP were localized toastrocytes and Müller cells. Neurons in the ganglion cell layer andinner nuclear layer were VEGF-immunopositive.Conclusions: This study identified some of the genes that aredifferentially regulated, probably in response to long-term IOPexposure, in this animal model. The expression pattern of many genes iscommon to experimental models of elevated IOP and other retinaldisorders such as diabetic retinopathy. However many genes are uniquelyexpressed in the retina of our model. This suggests that the mode of IOPelevation be it experimental or spontaneous could be relevant indetermining which genes are regulated. Müller glia acquire a reactivephenotype as indicated by the upregulation of GFAP, c-myc, SA, and otherMüller cell markers, emphasizing their relevance in pressure related-and other types of retinal injury. These data provide further evidencethat IOP-mediated retinal injury is multifactorial and depends upon theinteraction of different neuronal, glial, extracellular matrix, andvasogenic components.

[学科分类] 生物化学/生物物理