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Increased expression of glial cell line-derived neurotrophic factor protects against oxidative damage-induced retinal
Aling Dong1, JiKui Shen, Melissa Krause
1Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-9277, USA.
Abstract:
Oxidative damage contributes to retinal cell death in patients with age-related macular degeneration or retinitis pigmentosa. One approach to treatment is to identify and eliminate the sources of oxidative damage. Another approach is to identify treatments that protect cells from multiple sources of oxidative damage. In this study, we investigated the effect of increased expression of glial cell line-derived neurotrophic factor (GDNF) in three models of oxidative damage-induced retinal degeneration. Double transgenic mice with doxycycline-inducible expression of GDNF in the retina were exposed to paraquat, FeSO(4), or hyperoxia, all sources of oxidative damage and retinal cell death. Compared to controls, mice with increased expression of GDNF in the retina showed significant preservation of retinal function measured by electroretinograms, reduced thinning of retinal cell layers, and fewer TUNEL-positive cells indicating less retinal cell death. Mice over-expressing GDNF also showed less staining for acrolein, nitrotyrosine, and 8-hydroxydeoxyguanosine, indicating less oxidative damage to lipids, proteins, and DNA. This suggests that GDNF did not act solely to allow cells to tolerate higher levels of oxidative damage before initiation of apoptosis, but also reduced damage from oxidative stress to critical macromolecules. These data suggest that gene transfer of Gdnf should be considered as a component of therapy for retinal degenerations in which oxidative damage plays a role.
Insights
Glial cell line-derived neurotrophic factor (GDNF) protects retinal cells from oxidative damage in models of age-related macular degeneration and retinitis pigmentosa. Increased GDNF expression reduced cell death and oxidative damage, suggesting its therapeutic potential.
Area of Science:
- Ophthalmology
- Neuroscience
- Genetics
Background:
- Oxidative damage is a key factor in retinal cell death associated with age-related macular degeneration (AMD) and retinitis pigmentosa (RP).
- Current treatments focus on eliminating oxidative damage sources or enhancing cellular resistance.
- Glial cell line-derived neurotrophic factor (GDNF) is a neurotrophic factor with potential protective roles in the nervous system.
Purpose of the Study:
- To investigate the therapeutic effect of glial cell line-derived neurotrophic factor (GDNF) on oxidative damage-induced retinal degeneration.
- To evaluate GDNF's protective mechanisms against oxidative stress in retinal cells.
Main Methods:
- Utilized double transgenic mice with inducible retinal GDNF expression.
- Exposed mice to three oxidative stress models: paraquat, FeSO(4), and hyperoxia.
- Assessed retinal function (electroretinograms), cell survival (TUNEL assay), and molecular markers of oxidative damage (acrolein, nitrotyrosine, 8-hydroxydeoxyguanosine).
Main Results:
- GDNF overexpression significantly preserved retinal function and reduced retinal cell layer thinning.
- Fewer TUNEL-positive cells indicated reduced retinal cell death in GDNF-treated mice.
- Reduced levels of acrolein, nitrotyrosine, and 8-hydroxydeoxyguanosine demonstrated decreased oxidative damage to lipids, proteins, and DNA.
Conclusions:
- GDNF not only enhances cellular tolerance to oxidative stress but also actively reduces oxidative damage to critical macromolecules.
- Gene therapy with GDNF presents a promising strategy for treating retinal degenerations where oxidative damage is a contributing factor.
- These findings support the consideration of GDNF gene transfer as a therapeutic component for oxidative stress-related retinal diseases.
