TGF-β1 signaling protects retinal ganglion cells from oxidative stress via modulation of the HO-1/Nrf2 pathway

被引：26
作者：
Chen, Hsin-Yi [1 ]
Ho, Yi-Jung [2 ]
Chou, Hsiu-Chuan [3 ]
Liao, En-Chi [1 ]
Tsai, Yi-Ting [1 ]
Wei, Yu-Shan [1 ]
Lin, Li-Hsun [1 ]
Lin, Meng-Wei [1 ]
Wang, Yi-Shiuan [1 ]
Ko, Mei-Lan [2 ,3 ]
Chan, Hong-Lin [1 ]
机构：
[1] Natl Tsing Hua Univ, Inst Bioinformat & Struct Biol, Dept Med Sci, Hsinchu 300, Taiwan
[2] Natl Taiwan Univ Hosp, Dept Ophthalmol, Hsin Chu Branch, Hsinchu 300, Taiwan
[3] Natl Tsing Hua Univ, Dept Biomed Engn & Environm Sci, Hsinchu 300, Taiwan
来源：
CHEMICO-BIOLOGICAL INTERACTIONS | 2020年 / 331卷
关键词：
TGF-beta; 1; Retinal ganglion cells; Oxidative stress; HO-1/Nrf2; pathway; GROWTH-FACTOR-BETA; HEME OXYGENASE-1; NRF2; SUPPRESSION; ACTIVATION; EXPRESSION; GLAUCOMA; MODEL;
D O I：
10.1016/j.cbi.2020.109249
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
Oxidative stress provides a major contribution to the pathogenesis of glaucoma and may induce retinal ganglion cell (RGC) damage. Transforming growth factor beta (TGF-beta) has appeared as a neuroprotective protein in various indignities. However, the TGF-beta mechanism of protective effects against oxidative stress damage in RGCs still undetermined. In our research, we investigated the regulatory mechanisms and potential effects of TGF-beta 1 & TGF-beta 2 in hydrogen peroxide (H2O2)-stimulated oxidative stress of RGCs in vitro. By a series of cell functional qualitative analysis, such as MTT cell viability assay, wound healing ability assay, apoptosis assay, intracellular ROS detection, immunoblot analysis, intracellular GSH content, and high-resolution respirometry, we illustrated the cell state in oxidative stress-induced injury. Results of protein expression showed that TGF-beta 1 & TGF-beta 2 was upregulated in RGCs after H2O2 stimulation. Cell functional assays resulted that knockdown of TGF-beta 1 & TGF-beta 2 reduced survival rate whereas enhanced apoptosis and accumulation of reactive oxygen species (ROS). Especially TGF-beta 1 upregulation promoted the protein expression of aldehyde dehydrogenase 3A1 (ALDH3A1) and increased the activity of antioxidant and neuroprotection pathways. Additionally, TGF-beta 1 & TGF-beta 2 on antioxidant signaling was related to activation of heme oxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor (Nrf2), which are stress-response proteins. ROS accumulation followed by the accumulation of hypoxia-inducible factor (HIF-1 alpha) caused mitochondrial damage and led to neurodegeneration. In summary, our results demonstrated that TGF-beta 1 preserves RGCs from free radicals-mediated injury by upregulating the activation of Nrf2 expression and HO-1 signaling balance HIF-1 alpha upregulation, implying a prospective role of TGF-beta 1 in retinal neuroprotection-related therapies.
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页数：15
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