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.
引用
收藏
页数：15
相关论文
共 43 条
[11]   Distribution and expression of transforming growth factor-β and platelet-derived growth factor in the normal and glaucomatous monkey optic nerve heads [J].
Fukuchi, T ;
Ueda, J ;
Hanyu, T ;
Abe, H ;
Sawaguchi, S .
JAPANESE JOURNAL OF OPHTHALMOLOGY, 2001, 45 (06) :592-599
[12]   Rubus idaeus L. (red raspberry) blocks UVB-induced MMP production and promotes type I procollagen synthesis via inhibition of MAPK/AP-1, NF-κβ and stimulation of TGF-β/Smad, Nrf2 in normal human dermal fibroblasts [J].
Gao, Wei ;
Wang, Yu-shuai ;
Hwang, Eunson ;
Lin, Pei ;
Bae, Jahyun ;
Seo, Seul A. ;
Yan, Zhengfei ;
Yi, Tae-Hoo .
JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY, 2018, 185 :241-253
[13]   Intracellular GSH Depletion Triggered Mitochondrial Bax Translocation to Accomplish Resveratrol-Induced Apoptosis in the U937 Cell Line [J].
Guha, Prasun ;
Dey, Anindya ;
Sen, Rupashree ;
Chatterjee, Mitali ;
Chattopadhyay, Subrata ;
Bandyopadhyay, Sandip K. .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2011, 336 (01) :206-214
[14]   Transforming growth factor-β2 levels in aqueous humor of glaucomatous eyes [J].
Inatani, M ;
Tanihara, H ;
Katsuta, H ;
Honjo, M ;
Kido, N ;
Honda, Y .
GRAEFES ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY, 2001, 239 (02) :109-113
[15]   Dynamics of H2O2 availability to ARPE-19 cultures in models of oxidative stress [J].
Kaczara, Patrycja ;
Sarna, Tadeusz ;
Burke, Janice M. .
FREE RADICAL BIOLOGY AND MEDICINE, 2010, 48 (08) :1064-1070
[16]   Molecular mechanism of Nrf2 activation by oxidative stress [J].
Kang, KW ;
Lee, SJ ;
Kim, SG .
ANTIOXIDANTS & REDOX SIGNALING, 2005, 7 (11-12) :1664-1673
[17]   Antioxidant function of corneal ALDH3A1 in cultured stromal fibroblasts [J].
Lassen, Natalie ;
Pappa, Aglaia ;
Black, William J. ;
Jester, James V. ;
Day, Brian J. ;
Min, Elysia ;
Vasiliou, Vasilis .
FREE RADICAL BIOLOGY AND MEDICINE, 2006, 41 (09) :1459-1469
[18]   Retinal ganglion cell apoptotic pathway in glaucoma: initiating and downstream mechanisms [J].
Levkovitch-Verbin, Hani .
NEW TRENDS IN BASIC AND CLINICAL RESEARCH OF GLAUCOMA: A NEURODEGENERATIVE DISEASE OF THE VISUAL SYSTEM, PT A, 2015, 220 :37-57
[19]   Upregulation of LGALS1 is associated with oral cancer metastasis [J].
Li, Ji-Min ;
Tseng, Chien-Wei ;
Lin, Chi-Chen ;
Law, Ching-Hsuan ;
Chien, Yu-An ;
Kuo, Wen-Hung ;
Chou, Hsiu-Chuan ;
Wang, Wen-Ching ;
Chan, Hong-Lin .
THERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY, 2018, 10 :1-20
[20]   Hyaluronic acid-dependent protection against UVB-damaged human corneal cells [J].
Li, Ji-Min ;
Chou, Hsiu-Chuan ;
Wang, Ssu-Han ;
Wu, Chieh-Lin ;
Chen, Yi-Wen ;
Lin, Szu-Ting ;
Chen, Yu-Hua ;
Chan, Hong-Lin .
ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, 2013, 54 (06) :429-449
12345