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K. Banerjee, X. Yang, G. Tezel; Upregulation of TNF–A in Hypertensive Rat Eyes . Invest. Ophthalmol. Vis. Sci. 2005;46(13):3772.
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Purpose: To further determine the association of TNF–α signaling with glaucomatous neurodegeneration, in vivo, we studied the expression and cellular localization of TNF–α and TNF–R1, a death receptor, in hypertensive rat eyes. Methods: Intraocular pressure (IOP) elevation was induced in rats by saline injections into the limbal venous system. The degree of cumulative IOP exposure was estimated by first integrating IOP over time in the hypertensive eye, then subtracting the IOP–time integral from that in the control fellow eye. The percentage axon loss was expressed by comparing the estimated total number of optic nerve axons in the experimental eye relative to the control fellow eye. Alterations in the retinal expression of TNF–α and TNF–R1 were studied by RT–PCR and Western blot analysis in rat eyes matched for the cumulative IOP exposure and axon loss. In addition, cellular localization of TNF–α and TNF–R1 was studied in the histologic sections of the retina and optic nerve head using double immunolabeling techniques. Results: During the experimental period of up to 12 weeks, the most prominent IOP exposure occurred after 6 weeks. A dose–response effect of pressure on axon loss was detectable with a threshold for axon loss at a value of approximately 200 mmHg–days. There was an increase in retinal TNF–α expression in hypertensive eyes compared with the control eyes, which exhibited an association with the cumulative IOP exposure and axon loss. Using specific antibodies, the intensity of TNF–α immunolabeling and the number of labeled cells were also greater in the retina and optic nerve head sections from hypertensive eyes compared with the controls. Double immunofluorescence labeling demonstrated that similar to glaucomatous human eyes, increased immunolabeling for TNF–α in hypertensive rat eyes was mainly localized to glial cells. However, TNF–R1 immunolabeling was most prominent on retinal ganglion cells (RGCs) and their axons. Conclusions: Upregulation of TNF–α in hypertensive rat eyes, along with previous findings, suggests that the TNF–α signaling is associated with the experimental paradigm of glaucomatous neurodegeneration. The presence of TNF–R1 on RGCs and their axons makes them susceptible targets for the TNF–α–mediated events. However, in respect to diverse bioactivities of TNF–α, which can induce both cell death and survival signals, ongoing studies for the development of neuroprotective strategies in glaucoma should determine inhibiting the cell death signaling and/or amplifying the survival signaling in RGCs, rather than inhibiting the TNF–R1 binding.
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