Role of endothelin receptors in glaucomatous optic neuropathy

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DESCRIPTION (provided by applicant): Glaucoma is an optic neuropathy characterized by degeneration of the optic nerve, cupping of the optic disc and apoptosis of retinal ganglion cells, ultimately resulting in blindness. Elevated intraocular pressure (IOP) is a prominent risk factor as seen in primary open angle glaucoma (POAG). Normal tension glaucoma (NTG) patients also show sign of optic neuropathy even though they have "normal" IOPs. Both POAG and NTG patients show elevation of endothelin-1 (ET-1), a potent vasoactive peptide, in their aqueous humor and circulation respectively. Increasing evidence points to an involvement of ET-1 in mediating optic nerve damage in experimental models of glaucoma. For instance, continuous administration of small doses of ET-1 to the retrobulbar region of the optic nerve has been shown to produce optic neuropathy in primates. However, the mechanism by which ET-1 produces these deleterious effects are not understood. ET-1 acts through mainly two classes of G-protein coupled receptors, namely, the ETA and ETB receptors, which are B predominantly linked to the calcium and nitric oxide signaling pathways respectively. Recent observations indicate that there is an upregulation of endothelin B receptor expression in a rodent elevated IOP model of glaucoma. The broad goals of the proposal are to understand if endothelin receptors play a neurodegenerative role in an animal model of glaucoma. The overall hypothesis to be tested is that IOP elevation in rats produces increased ETB receptor expression in the retina which contributes to retinal B ganglion cell death. The following specific aims will be directed to addressing the above hypothesis: 1) Measure ETBB receptor expression in rat retinas following a time-dependent elevation of IOP rats using a combination of immunohistochemical and receptor binding studies. 2) Determine if retinal ganglion cell death following IOP elevation, is attenuated in ETB-B deficient rats, compared to wild type rats. This will be carried out by counting viable retrogradely labeled retinal ganglion cells following IOP elevation in wild type and ETB-B deficient rats. 3) Understand molecular mechanisms contributing to increase in ETBB expression in retinal ganglion cells by using promoter-reporter and electrophoretic mobility shift assays to identify cis-acting elements and trans-acting factors contributing to constitutive and inducible ETBB expression in the RGC-5 cell line. The DNA binding activity of transcription factors AP-1, C/EBP and SMAD 3/4 will also be studied in retinas of rats with elevated IOP and correlated with increased ETBB expression. These studies will provide valuable information on expression of the ETB receptor during glaucomatous optic B neuropathy and ETBB receptor mediated signaling that mediates apoptotic cell death of retinal ganglion cells. The information gained from this study could be useful in developing endothelin receptor antagonists as neuroprotective agents in glaucoma treatment. PUBLIC HEALTH RELEVANCE: The proposed study will determine if endothelin receptors produce some of the nerve damage seen in glaucoma. Understanding how endothelin receptors are damaging to nerve cells, will provide valuable information to block these receptors and thereby provide protection to nerve cells in the eye from further damage. This could lead to development of neuroprotection drugs as additional treatments to effectively treat glaucoma.