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Z. Wang, T.J. Bartosh, N. Agarwal, R.S. Roque; Human Retinal Progenitor Cells Inhibit Altered Expression of NRH2 and Retinal Ganglion Cell Death During Oxidative Stress . Invest. Ophthalmol. Vis. Sci. 2006;47(13):5767.
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© ARVO (1962-2015); The Authors (2016-present)
Neurotrophin receptor homologue 2 (NRH2) is a member of the tumor necrosis factor receptor superfamily that exhibits substantial sequence homology to the intracellular domain (ICD) of p75 neurotrophin receptor (p75NTR). Previous studies localizing p75NTR and NRH2 to retinal ganglion cells (RGC), findings of increased levels of p75NTR in degenerating RGC of animals with elevated intraocular pressure, and reports showing overexpression of p75ICD or NRH2 promoted neuronal apoptosis–––were all consistent with a role for NRH2 in RGC degeneration. In the following study, the effects of oxidative stress on the survival and expression of NRH2 in RGC were investigated. Moreover, the effects of trophic factors from human retinal progenitor cells (hRPCs) on NRH2 expression and RGC degeneration were established.
A hydrogen peroxide–generating culture system utilizing glucose oxidase/glucose was used to test the effects of oxidative stress on the survival and expression of NRH2 in RGC–5 cells, a well–characterized transformed rat retinal ganglion cell line. RGC–5 cells were grown in the above culture system in the presence or absence of 48h–conditioned media (CM) from hRPCs isolated from donor neonatal retinas. RGC–5 cell survival was determined by MTS assay and fluorescent dyes (calcein AM and ethidium homodimer); while JC–1 was used to determine mitochondrial membrane integrity. NRH2 expression was determined using immunological assays.
Increased expression of NRH2 was observed in RGC–5 following oxidative stress. Glucose oxidase/glucose treatment of RGC–5 resulted in a dose–dependent increase in cell death and increased mitochondrial membrane depolarization. CM from hRPCs inhibited RGC–5 cell death and collapse of mitochondrial membrane potential due to oxidative damage. Moreover, the CM inhibited altered expression of NRH2 in RGC–5 cells.
Our study shows that oxidative stress to retinal ganglion cells promoted increased expression of NRH2, increased mitochondrial membrane permeability, and retinal ganglion cell death. Moreover, human progenitor cells isolated from neonatal retinas secreted anti–apoptotic molecules that inhibited NRH2 changes and protected RGC from oxidative damage in vitro. Our study suggests that putative hRPC–derived trophic factors and NRH2 inhibitors could prove useful in neuroprotection of RGC from oxidative stress such as in glaucoma.
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