PURPOSE To characterize the changes in retinal gene expression induced by elevated intraocular pressure (IOP) in a hereditary rodent model. METHODS A rat model derived from the RCS-rdy- strain develops IOP elevation spontaneously without experimental manipulation. Retinal gene expression after IOP elevation was compared with age-matched RCS-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 expression of heat shock protein-27 (Hsp-27), SA hypertension-associated gene, c-myc, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), vascular endothelial 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 acidic protein (GFAP), VEGF, and SA was assessed using immunohistochemistry. RESULTS Elevated IOP of 37.7+/-5.0 mmHg shifted the retina's program of gene expression, with 75 genes being upregulated (equal to or higher than 3.0 fold) and 45 genes being downregulated (equal to or lower than 0.3 fold). These genes mediate various cellular processes such as cell adhesion, cell structure, hypertension, immunity, protein sythesis, proteolysis, transcription, and signaling. The regulation pattern of SA, VEGF, c-myc, IL-7, and MAPK-13, which are uniquely regulated in our model were confirmed by qRT-PCR experiments. The regulation of Hsp-27, TIMP-1, myocilin, and Cryba1, which have previously been associated with elevated IOP were also confirmed with qRT-PCR. The protein products of c-myc, SA, and GFAP were localized to astrocytes and Müller cells. Neurons in the ganglion cell layer and inner nuclear layer were VEGF-immunopositive. CONCLUSIONS This study identified some of the genes that are differentially regulated, probably in response to long-term IOP exposure, in this animal model. The expression pattern of many genes is common to experimental models of elevated IOP and other retinal disorders such as diabetic retinopathy. However many genes are uniquely expressed in the retina of our model. This suggests that the mode of IOP elevation be it experimental or spontaneous could be relevant in determining which genes are regulated. Müller glia acquire a reactive phenotype as indicated by the upregulation of GFAP, c-myc, SA, and other Müller cell markers, emphasizing their relevance in pressure related- and other types of retinal injury. These data provide further evidence that IOP-mediated retinal injury is multifactorial and depends upon the interaction of different neuronal, glial, extracellular matrix, and vasogenic components.