Abstract
Abstract: :
Purpose: Retinitis pigmentosa (RP) comprises a heterogenous group of inherited diseases that are characterised by primary degeneration of rod photoreceptors and secondary degeneration of cone photoreceptors in the retina, and additional pathologic changes include vascular changes and invasion of the inner retina by retinal pigment epithelial (RPE) cells. RP represents a major cause of progressive retinal disease worldwide. Tissues of the central nervous system, including the brain and retina, depend on intact blood–brain and blood–retinal barriers (BRB), respectively, to partition them from the systemic circulation. The BRB consists of the inner BRB (iBRB) and the outer BRB (oBRB) with the endothelial cell tight junctions of the retinal vessels forming the iBRB and the tight junctions of the RPE and Bruchs membrane the main structures involved in forming the oBRB. Methods: Using a mouse model of RP with retinopathy induced by targeted disruption of the rhodopsin gene (Rho–/–), we have used western blot analysis, real–time PCR and immunohistochemical staining of retinal cryosections to analyse changes in levels of expression of tight junction and adherens junction proteins and transcripts. Results: We have found an up–regulation of the tight junction protein ZO–1 at the BRB in Rho–/– mice compared with wildtype animals from a C–129 background, and a change in levels of expression of E–cadherin, suggesting loss of integrity of BRB function. Upon separation of retinas into predominantly neural lysates and RPE lysates, we have found these increases in protein expression to be localised to the neural tissue. Increased transcripts of genes encoding TJ–associated molecules CDC42 and α–catenin were also present in retinas from the knock–out mice. Conclusions: We hypothesise that BRB integrity may be affected following photoreceptor cell death and retinal changes following photoreceptor cell death may contribute to pathogenesis. Our findings of changes in levels of expression of ZO–1, which has a scaffolding function, and of ZO–1–associated proteins, in 6 week old Rho–/– mice provide evidence for early iBRB modifications in an animal model of RP.
Keywords: cell adhesions/cell junctions • cell-cell communication • retinitis