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B. Liu, H. Chen, A. H. Neufeld; Upregulation of Gadd45b in the Aging Retina. Invest. Ophthalmol. Vis. Sci. 2007;48(13):46.
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There is an age-related loss of neurons in the retina. We compared young and old mice retinas using microarray analyses and found that there is a significant increase in the expression of the gene for growth arrest and DNA damage-inducible (Gadd45b) protein. Associated with apoptosis, this is an intrinsic anti-apoptosis pathway important in control of the cell cycle in response to genotoxic stresses and apoptotic cytokines. In this study, we demonstrate Gadd45b expression, localization and regulation in the aging retina.
Gadd45b expression in the retina was detected by quantitative real time RT-PCR for mRNA and by immunoblot for protein. Cells expressing Gadd45b were detected by immunohistochemistry. The upstream signal of Gadd45b, NFkB-IkB was detected by immunoblot and immunohistochemistry for phosphorylation of IkB. We also determined the regulation of Gadd45b in the retina in response to an oxidative stress produced by IP injection of paraquat.
Compared to young mice (5 months), the aging retina of old mice (25 months) has significantly higher levels of Gadd45b mRNA. Immunohistochemical labeling for Gadd45b protein localized Gadd45b specifically to retinal ganglion cells (RGCs) and not in other retinal layers. Immunolabeling for Gadd45b is weakly present in a few RGCs in young retinas but significantly increased in intensity in an abundant number of RGCs in old retinas. Activation of NFkB-IkB up-regulates the transcription of Gadd45b gene. We detected significantly increased activation of NFkB (phosphorylation of IkB) in RGCs in the aged retina. Under paraquat induced oxidative stress, Gadd45b expression and IkB phosphorylation are significantly increased in RGCs. These results demonstrate that Gadd45b expression is upregulated by activation of NFkB in RGCs of the aging retina and that upregulation of Gadd45b expression occurs in response to oxidative stress.
The Gadd45b signaling pathway is a specific stress response pathway that may be protective of RGCs in an age-dependent pattern and may reflect increased oxidative stress during aging. Our findings may provide a potential strategy for regulating the Gadd45b signaling pathway to prevent the loss of RGCs in the aging retina and possibly other neurons in the CNS as well.
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