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| December 2003 | Inside IOVS | Volume 44/12 |
MPP4 in the Mammalian Retina
MPP4 is a retina-specific member of the membrane-associated guanylate kinases (MAGUKs), a family of scaffolding proteins known to mediate the assembly and maintenance of specialized membrane domains in polarized cells. By immunofluorescence microscopy, Stöhr et al. (p. 5067) localized the MPP4 protein to synaptic terminals in the outer and inner plexiform layers in bovine and porcine retinae. In addition, strong labeling of the photoreceptor connecting cilia was observed making MPP4 the first known MAGUK protein expressed in ciliary structures. Extraction studies indicate a link of MPP4 with cytoskeletal elements. Taken together, these data suggest that MPP4 is part of membrane-cytoskeletal complexes in distinct structural and functional compartments of the mammalian retina.
Pathways Regulating Matrix Metalloproteinase Expression in Trabecular Meshwork
Trabecular meshwork cells appear to sense elevated intraocular pressure (IOP) as mechanical stretching of their extracellular matrix (ECM) and respond by increasing select matrix metalloproteinase (MMP) expression and activity. This initiates ECM turnover, which appears to adjust the outflow resistance and provide a homeostatic mechanism for maintaining IOP. Signaling pathways involved in modulating this process are explored by Bradley et al. (p. 5174). Integrin linked kinase and phosphoinositide-dependent kinase phosphorylate and activate protein kinase B. The mammalian target of rapamycin, mTOR, and p70 S6 kinase are downstream kinases in this process. These signaling cascades converge on specific steps regulating initiation of protein translation of MMP-2 and MMP-14. These results provide possible new sites for intervention in the process of glaucomatous IOP elevation.
Retinal Ganglion Cell Survival by IL-10
Glaucoma is a group of disorders that can lead to optic nerve damage and results in blindness caused by the apoptosis of retinal ganglion cells (RGCs). Boyd et al. (p. 5206) studied the effect of various cytokines on the survival of RGCs in culture and discovered that IL-10 promotes the survival of RGCs after the specific neuronal insult of serum deprivation or oxidative stress. Their results indicate that activation of the IL-10 receptor inhibits the apoptosis of RGCs by stimulating the STAT-3 signaling pathway. An understanding of molecular pathways responsible for IL-10 mediated RGC survival may yield novel therapies to regulate RGC death in glaucoma.
Inhibition of TNF-a mRNA Prevents Local Immunopathology
TNF-a is a pleiotrophic cytokine involved in many inflammatory diseases and plays a key role in herpetic stromal keratitis. Wasmuth et al (p. 5228) show that application of antisense oligonucleotides targeting this cytokine prevented the development of experimental blinding stromal keratitis, while clearance of replicative virus particles was not impaired. Inhibition of local TNF-a may thus represent a new approach to the treatment of corneal disorders associated with ocular immunopathologic diseases.
Endothelin – Glucocorticoid Interactions in the Anterior Segment
Both endothelin-1 (ET-1) and glucocorticoids have been linked to glaucoma. Previously, the authors demonstrated that the glucocorticoid dexamethasone (dex) stimulates ET-1 release from human non-pigmented ciliary epithelial cells (HNPE). In the present study, Zhang et al. (p. 5301) demonstrate that dex not only increases the release of ET-1 from HNPE source cells but also produces a decrease in the expression of ETB receptors in trabecular meshwork cells (TM) while the ETA receptor expression remains unchanged. These receptor changes were also reflected in signaling molecules where calcium mobilization was unchanged but ETB receptor nitric oxide production decreased in response to ET-1. These actions would result in decreased relaxation of the TM and increased contraction. Such effects would contribute to the decline in conventional aqueous humor outflow and increases in intraocular pressure often seen with glucocorticoid treatment.
Pathophysiology Associated with Retinal Neovascularization
Newborn rodents are commonly used to study the factors involved in the development of retinal neovascularization (NV), although little is known about the associated pathophysiology. Roberts et al. (p. 5315), using a magnetic resonance based oxygenation response measurement, found distinct differences between the spatial and temporal retinal oxygenation patterns in the mouse NV model and the previously reported rat NV model. In the understanding of mechanisms underlying retinal neovascularization, and in the search for successful treatment options, identification of such differences may be of value.
MMP-2, but not MMP-9, Is Involved in Retinal Neovascularization
Matrix metalloproteinases (MMPs) have important roles in the regulation of endothelial cell migration and extracellular matrix remodeling during angiogenesis. Ohno-Matsui et al. (p. 5370) demonstrate that retinal neovascularization is significantly reduced in MMP-2-deficient mice as compared to wild-type mice using oxygen-induced retinopathy model. However, there is no significant difference in angiogenic response between MMP-9 deficient mice and wild-type mice. This indicates that MMP-2 might be important for the regulation of retinal neovascularization. Pharmacologic intervention using inhibitors specific to MMP-2 might be a future therapeutic approach for angiogenic retinal diseases.
Paracellular Vascular Permeability in Diabetes
Diabetes increases vascular permeability in the retina; however, both transcellular and paracellular routes have been proposed to account for this increased permeability. By using a novel lectin perfusion technique, Barber and Antonetti (p. 5410) show that the paracellular route contributes to the increase in vascular permeability in diabetes. Using the fluorescently tagged plant lectin, concanavalin A, the authors decorated regions of paracellular permeability (green) in whole mount retinas. The retinas were counter stained for the tight junction protein occludin (red) demonstrating loss of tight junction integrity at regions of paracellular permeability after one month of diabetes.
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