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Raghu R Krishnamoorthy, Alena Z Minton, Shaoqing He, Nolan Robert McGrady, Dorota L Stankowska; Endothelin Receptor Mediated Neurodegeneration in a Rodent Model of Glaucoma.. Invest. Ophthalmol. Vis. Sci. 2016;57(12):No Pagination Specified.
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© ARVO (1962-2015); The Authors (2016-present)
Previous studies showed that neurodegenerative changes following intraocular pressure (IOP) elevation, including, degeneration of optic nerve axons and retinal ganglion cell (RGC) loss were greatly attenuated in ETB receptor-deficient transgenic Wistar Kyoto rats, compared to wild type rats. The current study determined whether there are any changes in expression of the immediate early gene c-Jun and apoptotic factors Bax and Bid, following IOP elevation in wild type and ETB receptor-deficient rats Additional studies were carried out to determine if the dual ETA/ETB receptor antagonist, macitentan could attenuate neurodegenerative changes following IOP elevation in Brown Norway rats.
IOP was elevated in one eye of adult wild type and ETB receptor-deficient rats using the Morrison’s method (injection of hypertonic saline through episcleral veins), while the contralateral eye served as control. Following IOP elevation, rats were maintained for 2 weeks and sacrificed. Rat eyes were subjected to laser capture microdissection (LCM) to capture RGC layers, followed by Real-time PCR using cDNA as template to detect gene expression of c-jun, bax and bid. In separate experiments, retinal sections were stained with specific antibodies to detect the protein expression of c-Jun and Bax by immunohistochemistry in IOP elevated wild type and ETB receptor-deficient rats. Another set of Brown Norway rats were fed for 1 month with macitentan (10 mg/kg/body weight) following IOP elevation (100 to 120 mm Hg-days). Retinal flat mounts obtained from the rats were assessed for RGC survival by immunostaining for the RGC marker RNA Binding Protein with Multiple Splicing (RBPMS).
Following 2 weeks of IOP elevation, there was a significant attenuation of c-jun, bax and bid mRNA expression in RGCs of ETB receptor-deficient rats, compared to those of wild type rats. Moreover, there was a marked decrease in protein levels of c-Jun and Bax in RGCs in ETB receptor-deficient rats, compared to wild type rats. Rats fed with macitentan displayed increased RGC survival following IOP elevation, compared to untreated rats.
Decreased expression of c-Jun, Bax, and Bid contribute to enhanced RGC survival in ETB receptor-deficient rats following IOP elevation. Blocking endothelin receptor activation could have neuroprotective effects without affecting IOP, possibly through blocking apoptotic pathways.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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