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B. Liu, G. Suyeoka, A. H. Neufeld; Intrinsic Tgfβ/Gadd45b NeuroprotectivePathway in Retinal Ganglion Cells. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5506. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
We hypothesize that retinal ganglion cells (RGCs) have intrinsic neuroprotective mechanisms that can be potentiated to increase their resistance to injury, as in glaucoma. Growth arrest and DNA damage inducible protein 45b (Gadd45b) is an anti-apoptosis protein important in cell survival in response to genotoxic stresses and apoptotic cytokines. We previously found that Gadd45b was upregulated by TGFβ signaling in RGCs. In this study, we demonstrate the neuroprotective function of the TGFβ/Gadd45b pathway and identify modulators that potentiate TGFβ/Gadd45b signaling in RGCs.
Gadd45b expression was detected by immunohistochemistry in retinas of glaucoma rat models. RGC5 cells were used for studies in vitro. Gadd45b SiRNA was transfected into RGC5 cells to knockdown Gadd45b. Gadd45b mRNA expression in RGC5 cells was detected by quantitative real time RT-PCR. The neuroprotective function of TGFβ/Gadd45b was demonstrated by comparing viable cell number among control, Gadd45b knockdown and TGFβ1 treated RGC5 cells exposed to TNFα cytotoxicity, glutamate excitotoxicity or paraquat oxidative stress. The modulation of the TGFβ/Gadd45b signal pathway was detected by immunoblot.
Gadd45b expression is specifically upregulated in RGCs in eyes with chronic, moderately elevated intraocular pressure compared to control eyes. Gadd45b expression is apparently induced by TGFβ signaling of RGCs in glaucomatous retinas. Comparing control and Gadd45b-knockdown RGC5 cells, knockdown of Gadd45b expression causes a much greater loss of RGC5 cells in response to TNFα cytotoxicity, glutamate excitotoxicity or paraquat oxidative stress. In TGFβ1 induced neuroprotection, induction of Gadd45b is an important component to protect cells from death. Co-treatment with resveratrol significantly potentiates the expression of Gadd45b and the neuroprotective effects of TGFβ1 against TNFα cytotoxicity in RGC5. Resveratrol modulates the TGFβ/Gadd45b signal transduction pathway by quickly increasing TGFβ receptor I and decrease TGFβ receptor II levels in RGC5 cells.
Gadd45b is an intrinsic, neuroprotective molecule that protects RGCs against mulitiple neuronal injuries. Gadd45b is induced by TGFβ signaling and can by potentiated by resveratrol. Resveratrol potentiates the TGFβ/Gadd45b signaling and the neuroprotective effect by increasing TGFβ receptor I level. Our findings provide a neuroprotective strategy to potentiate an intrinsic neuroprotective mechanism in RGCs for the treatment of glaucoma and possibly other neurodegenerations as well.
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