Effect of tert-Butylhydroquinone on the expression of nuclear factor erythroid 2-related factor 2, heme oxygenase-1 and phosphatidylinositol 3-kinase in high glucose cultured retinal Müller cells_Chinese Journal of Ocular Fundus Diseases

Authors：

Tian Min , Wu Jinchuan , He Wei , Yu Xi ,  Lyu Hongbin

Department of Ophthalmology, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China;

Corresponding author：

Lyu Hongbin, Email: oculistlvhongbin@163.com

Keywords：

Hydroquinones; NF-E2-related factor 2; Heme oxygenase (decyclizing); Phosphatidylinositol 3-kinase; Müller cell

DOI：

10.3760/cma.j.issn.1005-1015.2018.04.015

Video：

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ObjectiveTo observe the effect of tert-Butylhydroquinone (tBHQ) on the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase (HO)-1 and phosphatidylinositol 3-kinase (PI3K) in high glucose cultured retinal Müller cells; and to investigate the anti-oxidative stress and anti-apoptotic effects of tBHQ.MethodsRetinal Müller cells were divided into normal glucose group (5.5 mmol/L, N group), high glucose group (45 mmol/L, HG group) and tBHQ intervention group (HG+tBHQ group). After retinal Müller cells were cultured with high glucose for 48 hours, the pretreatment with tBHQ (20 μmol/L) induced the expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and HO-1. The Müller cells were identified by immunofluorescence staining. The expressions of Nrf2, HO-1, PI3K, B-cell lymphoma-2 (Bcl-2) and Bax were detected by Western blot and real-time fluorescence quantitative PCR. Flow cytometry was used to detect the apoptosis of retinal Müller cells in rats.ResultsMüller cytoplasm and nucleus GS showed strong positive, large cell body, abundant cytoplasm, uniform green fluorescence; nuclear DAPI staining round or oval, clear boundary. The expression of Nrf2 protein (t=4.114, P=0.006), HO-1 protein (t=9.275, P=0.000), Nrf2 mRNA (t=7.292, P=0.000) and HO-1 mRNA (t=15.014, P=0.000) in the HG group were higher than those in the N group. The expressions of Nrf2 protein (t=7.847, P=0.000) ,HO-1 protein (t=7.947, P=0.000), PI3K protein (t=5.397, P=0.002), Bcl-2 protein (t=6.825, P=0.000), Nrf2 mRNA (t=18.046, P=0.000), HO-1 mRNA (t=39.458, P=0.000), PI3K mRNA (t=4.979, P=0.003) and Bcl-2 mRNA (t=9.535, P=0.000) in the HG+tBHQ group were significantly higher than those in the HG group. The protein and mRNA expressions of Bax protein in the HG+tBHQ group were significantly lower than those in the HG group (t=14.998, 16.520; P=0.000, 0.000). Flow cytometry showed that the apoptosis rate of Müller cells in the HG group was significantly higher than that in the N group (t=39.905, P=0.000). The apoptosis rate of Müller cells in the HG+tBHQ group was significantly lower than that in the HG group (t=21.083, P=0.000).ConclusiontBHQ can inhibit the apoptosis of retinal Müller cells by up-regulating the expression of Nrf2, HO-1 and PI3K.

Citation： Tian Min, Wu Jinchuan, He Wei, Yu Xi, Lyu Hongbin. Effect of tert-Butylhydroquinone on the expression of nuclear factor erythroid 2-related factor 2, heme oxygenase-1 and phosphatidylinositol 3-kinase in high glucose cultured retinal Müller cells. Chinese Journal of Ocular Fundus Diseases, 2018, 34(4): 382-387. doi: 10.3760/cma.j.issn.1005-1015.2018.04.015 Copy

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2.	Dinkova-kostova AT, Wang XJ. Induction of the keap1/nrf2/are pathway by oxidizable diphenols[J]. Chem Biol Interact, 2011, 192(1-2): 101-106.DOI: 10.1016/j.cbi.2010.09.010.
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13.	李晶艳, 田敏, 张思远, 等.叔丁基对苯二酚对2型糖尿病大鼠视网膜核因子E2相关因子、血红素氧合酶1表达的影响[J].中华眼底病杂志, 2015, 31 (6): 581-585. DOI: 10.3760/cma.j.issn.1005-1015.2015.06.017.Li JH, Tian M, Zhang SY, et al.The influence of tert-butyl hydroquinone on retinal nuclear factor E2-related factor 2 and heme oxygenase-1 in type 2 diabetic rats[J].Chin J Ocul Fundus Dis, 2015, 31(6): 581-585.DOI: 10.3760/cma.j.issn.1005-1015.2015.06.017.
14.	Han N, Yu L, Song Z, et al. Agmatine protects Müller cells from high-concentration glucose-induced cell damage via N-methyl-D-aspartic acid receptor inhibition[J]. Mol Med Rep, 2015, 12(1): 1098-1106.DOI: 10.3892/mmr.2015.3540.
15.	Shih AY, Li P, Murphy TH. A small-molecule-inducible Nrf2-mediated antioxidant response provides effective prophylaxis against cerebral ischemia in vivo[J]. J Neurosci, 2005, 25(44): 10321-10335.DOI: 10.1523/JNEUROSCI.4014-05.2005.
16.	宋明霞, 谢学军, 万李, 等.高糖及糖基化终末产物对视网膜Müller细胞缺氧诱导因子-1α介导缺氧信号通路的影响[J]. 眼科新进展, 2013, 33(12): 1101-1105.Song MX, Xie XJ, Wan Li, et al.Effects of high glucose and AGEs on hypoxia signal pathway mediated by HIF-1α of retinal Müller cells[J].Rec Adv Ophthalmol, 2013, 33(12): 1101-1105.
17.	郭敬, 柯敏, 文小凤.高糖对体外培养的视网膜Müller细胞活性的影响[J].中华实验眼科杂志, 2012, 30(9) 791-794.DOI: 10.3760/cma.j.issn.2095-0160.2012.09.006.Guo J, Ke M, Wen XF.Effect of high glucose on cultured retinal Müller cell in vitro[J].Chin J Exp Ophthalmol, 2012, 30(9) 791-794.DOI: 10.3760/cma.j.issn.2095-0160.2012.09.006.
18.	Xu Z, Wei Y, Gong J, et al. NRF2 plays a protective role in diabetic retinopathy in mice[J]. Diabetologia, 2014, 57(1): 204-213.DOI: 10.1007/s00125-013-3093-8.
19.	Zhong Q, Mishra M, Kowluru RA.Transcription factor Nrf2-mediated antioxidant defense system in the development of diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 2013, 54(6): 3941-3948.DOI: 10.1167/iovs.13-11598.
20.	Suzuki T, Yamamoto M. Molecular basis of the Keap1-Nrf2 system[J].Free Radic Biol Med, 2015, 88(Part B): 93-100. DOI: 10.1016/j.freeradbiomed.2015.06.006.
21.	Zhang H, Davies KJA, Forman HJ. Oxidative stress response and Nrf2 signaling in aging [J].Free Radic Biol Med, 2015, 88(Pt B): 314-336. DOI: 10.1016/j.freeradbiomed.2015.05.036.
22.	Prasad KN. Simultaneous activation of Nrf2 and elevation of antioxidant compounds for reducing oxidative stress and chronic inflammation in human Alzheimer’s disease[J].Mech Ageing Dev, 2016, 153: 41-47.DOI: 10.1016/j.mad.2016.01.002.
23.	Dreger H, Westphal K, Weller A, et al. Nrf2-depengdent upregulation of antioxidative enzymes: a novel pathway for proteasome inhibitor-mediated cardioprotection[J].Caidiovasc Res, 2009, 83(2): 354-361.DOI: 10.1093/cvr/cvp107.
24.	Shen G, Jeong WS, Hu R, et al. Regulation of Nrf2, NF-kappaB, and AP-1 signaling pathways by chemopreventive agents[J]. Antioxid Redox Signal, 2005, 7(7): 1648-1663. DOI: 10.1089/ars.2005.7.1648.
25.	Korsmeyer SJ, Shutter JR, Veis DJ, et al. Bcl-2/Bax: a rheostat that regulates an anti-oxidant pathway and cell death[J]. Semin Cancer Biol, 1993, 4: 327-32.
26.	Korsmeyer SJ. Bcl-2 gene family and the regulation of programmed cell death[J]. Cancer Res, 1999, 59(7 Suppl): S1693-1700.
27.	Podestà F, Romeo G, Liu WH, et al. Bax is increased in the retina of diabetic subjects and is associated with pericyte apoptosis in vivo and in vitro[J]. Am J Pathol, 2000, 156(3): 1025-1032. DOI: 10.1016/S0002-9440(10)64970-X.
28.	Shen J, Wu Y, Xu JY, et al. ERK-and Akt-dependent neuroprotection by erythropoietin (EPO) against glyoxal-AGEs via modulation of Bcl-xL, Bax and BAD[J]. Invest Ophthalmol Vis Sci, 2010, 51(1): 35-46. DOI: 10.1167/iovs.09-3544.
29.	Oshitari T, Yamamoto S, Hata N, et al. Mitochondria-and caspase-dependent cell death pathway involved in neuronal degeneration in diabetic retinopathy[J]. Br J Ophthalmol, 2008, 92(4): 552-556.DOI: 10.1136/bjo.2007.132308.
30.	Kusner LL, Sarthy VP, Mohr S. Nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase: a role in high glucose-induced apoptosis in retinal Müller cells[J]. Invest Ophthalmol Vis Sci, 2004, 45(5): 1553-1561.
31.	Mohr S, Xi X, Tang J, et al. Caspase activation in retinas of diabetic and galactosemic mice and diabetic patient[J]. Diabetes, 2002, 51(4): 1172-1179.
32.	Wang L, Chen Y, Sternberg P, et al. Essential roles of the PI3 kinase/Akt pathway in regulating Nrf2-dependent antioxidant functions in the RPE[J]. Invest Ophthalmol Vis Sci, 2008, 49: 1671-1678.
33.	Papaiahgari S, Zhang Q, Kleeberger SR, et al. Hyperoxia stimulates an Nrf2-ARE transcriptional response via ROS-EGFR-PI3K-Akt/ERK MAP kinase signaling in pulmonary epithelial cells[J]. Antioxid Redox Signal, 2006, 8(1-2): 43-52. DOI: 10.1089/ars.2006.8.43.
34.	Zhang H, Forman HJ. Acrolein induces heme oxygenase-1 through PKC-delta and PI3K in human bronchial epithelial cells[J]. Am J Respir Cell Mol Biol, 2008, 38(4): 483-490. DOI: 10.1165/rcmb.2007-0260OC.
35.	Jiang T, Chang Q, Zhao Z, et al. Melatonin-mediated cytoprotection against hyperglycemic injury in Müller cells[J/OL]. PLoS One, 2012, 7(12): 50661[2012-12-04]. https://doi.org/10.1371/journal.pone.0050661.DOI:10.1371/journal.pone.0050661.
36.	Niture SK, Jaiswal AK.Nrf2 protein up-regulates antiapoptotic protein bcl-2 and prevents cellular apoptosis[J]. J Biol Chem, 2012, 287(13): 9873-9886.DOI: 10.1074/jbc.M111.312694.
37.	Li S, Li J, Shen C, et al. Tert-butylhydroquinone (tBHQ) protects hepatocytes against lipotoxicity via inducing autophagy independently of Nrf2 activation[J]. Biochim Biophys Acta, 2014, 1841(1): 22-33. DOI: 10.1016/j.bbalip.2013.09.004.
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1. Kowluru RA, Chan PS. Oxidative stress and diabetic retinopathy[J/OL]. Exp Diabetes Res, 2007, 2007: 43603[2007-02-08].http://dx.doi.org/10.1155/2007/43603.DOI: 10.1155/2007/43603.
2. Dinkova-kostova AT, Wang XJ. Induction of the keap1/nrf2/are pathway by oxidizable diphenols[J]. Chem Biol Interact, 2011, 192(1-2): 101-106.DOI: 10.1016/j.cbi.2010.09.010.
3. Reiter C. E. Gardner T. W. Functions of insulin and insulin receptor signaling in retina: possible implications for diabetic retinopathy. Prog. Retin[J]. Eye Res, 2003, 22: 545-562.
4. Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream[J]. Cell, 2007, 129: 1261-1274. DOI: 10.1016/j.cell.2007.06.009.
5. del Peso L, González-García M, Page C, et al. Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt[J]. Science, 1997, 278: 687-689.
6. Fletcher JI, Huang DC. Controlling the cell death mediators Bax and Bak: puzzles and conundrums[J]. Cell Cycle, 2008, 7: 39-44. DOI: 10.4161/cc.7.1.5178.
7. Steelman LS, Abrams SL, Whelan J, et al. Contributions of the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to leukemia[J]. Leukemia, 2008, 22: 686-707. DOI: 10.1038/leu.2008.26.
8. Kang KW, Lee SJ, Park JW, et al. Phosphatidylinositol 3-kinase regulates nuclear translocation of NF-E2-related factor 2 through actin rearrangement in response to oxidative stress[J]. Mol Pharmacol, 2002, 62(5): 1001-1010.
9. Kraft AD, Johnson DA, Johnson JA. Nuclear factor E2-related factor 2-dependent antioxidant response element activation by tert-butylhydroquinone and sulforaphane occurring preferentially in astrocytes conditions neurons against oxidative insult[J]. J Neurosci, 2004, 24(5): 1101-1112. DOI: 10.1523/JNEUROSCI.3817-03.2004.
10. 田敏, 张思远, 韩佩晏, 等.叔丁基对苯二酚激活Nrf2信号通路增强对2型糖尿病大鼠视网膜的保护作用[J].眼科新进展, 2017, 37(3): 220-224.DOI: 10.13389/j.cnki.rao.2017.0056.Tian M, Zhang SY, Han PY, et al.tBHQ activates Nrf2 signaling pathways to enhance retinal protection in type 2 diabetic rats[J].Rec Adv Ophthalmol, 2017, 37(3): 220-224. DOI: 10.13389/j.cnki.rao.2017.0056.
11. 张思远, 田敏, 李晶艳, 等.tBHQ对2型糖尿病大鼠视网膜HO-1、VEGF表达及胰岛功能作用的研究[J].中华眼科杂志, 2016, 52(5): 373-381. DOI: 10.3760/cma.j.issn.0412-4081.2016.05.012.Zhang SY, Tian M, Li JY, et al.Influence of tert-butylhydroquinone on the islets function and expression of HO-1 and VEGF in retina of type 2 diabetic rats[J].Chin J Ophthalmol, 2016, 52(5): 373-381.DOI: 10.3760/cma.j.issn.0412-4081.2016.05.012.
12. 韩佩晏, 张思远, 李晶艳, 等.叔丁基对苯二酚对2型糖尿病大鼠视网膜细胞的保护作用及其机制[J].中华实验眼科杂志, 2016, 34(6): 496-502. DOI: 10.3760/cma.j.issn.2095-0160.2016.06.004.Han PY, Zhang SY, Li JY, et al.Protecting effects and mechanism of tert-butyl hydroquinone on retinal cells in type 2 diabetic rats[J].Chin J Exp Ophthalmo, 2016, 34(6): 496-502. DOI: 10.3760/cma.j.issn.2095-0160.2016.06.004.
13. 李晶艳, 田敏, 张思远, 等.叔丁基对苯二酚对2型糖尿病大鼠视网膜核因子E2相关因子、血红素氧合酶1表达的影响[J].中华眼底病杂志, 2015, 31 (6): 581-585. DOI: 10.3760/cma.j.issn.1005-1015.2015.06.017.Li JH, Tian M, Zhang SY, et al.The influence of tert-butyl hydroquinone on retinal nuclear factor E2-related factor 2 and heme oxygenase-1 in type 2 diabetic rats[J].Chin J Ocul Fundus Dis, 2015, 31(6): 581-585.DOI: 10.3760/cma.j.issn.1005-1015.2015.06.017.
14. Han N, Yu L, Song Z, et al. Agmatine protects Müller cells from high-concentration glucose-induced cell damage via N-methyl-D-aspartic acid receptor inhibition[J]. Mol Med Rep, 2015, 12(1): 1098-1106.DOI: 10.3892/mmr.2015.3540.
15. Shih AY, Li P, Murphy TH. A small-molecule-inducible Nrf2-mediated antioxidant response provides effective prophylaxis against cerebral ischemia in vivo[J]. J Neurosci, 2005, 25(44): 10321-10335.DOI: 10.1523/JNEUROSCI.4014-05.2005.
16. 宋明霞, 谢学军, 万李, 等.高糖及糖基化终末产物对视网膜Müller细胞缺氧诱导因子-1α介导缺氧信号通路的影响[J]. 眼科新进展, 2013, 33(12): 1101-1105.Song MX, Xie XJ, Wan Li, et al.Effects of high glucose and AGEs on hypoxia signal pathway mediated by HIF-1α of retinal Müller cells[J].Rec Adv Ophthalmol, 2013, 33(12): 1101-1105.
17. 郭敬, 柯敏, 文小凤.高糖对体外培养的视网膜Müller细胞活性的影响[J].中华实验眼科杂志, 2012, 30(9) 791-794.DOI: 10.3760/cma.j.issn.2095-0160.2012.09.006.Guo J, Ke M, Wen XF.Effect of high glucose on cultured retinal Müller cell in vitro[J].Chin J Exp Ophthalmol, 2012, 30(9) 791-794.DOI: 10.3760/cma.j.issn.2095-0160.2012.09.006.
18. Xu Z, Wei Y, Gong J, et al. NRF2 plays a protective role in diabetic retinopathy in mice[J]. Diabetologia, 2014, 57(1): 204-213.DOI: 10.1007/s00125-013-3093-8.
19. Zhong Q, Mishra M, Kowluru RA.Transcription factor Nrf2-mediated antioxidant defense system in the development of diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 2013, 54(6): 3941-3948.DOI: 10.1167/iovs.13-11598.
20. Suzuki T, Yamamoto M. Molecular basis of the Keap1-Nrf2 system[J].Free Radic Biol Med, 2015, 88(Part B): 93-100. DOI: 10.1016/j.freeradbiomed.2015.06.006.
21. Zhang H, Davies KJA, Forman HJ. Oxidative stress response and Nrf2 signaling in aging [J].Free Radic Biol Med, 2015, 88(Pt B): 314-336. DOI: 10.1016/j.freeradbiomed.2015.05.036.
22. Prasad KN. Simultaneous activation of Nrf2 and elevation of antioxidant compounds for reducing oxidative stress and chronic inflammation in human Alzheimer’s disease[J].Mech Ageing Dev, 2016, 153: 41-47.DOI: 10.1016/j.mad.2016.01.002.
23. Dreger H, Westphal K, Weller A, et al. Nrf2-depengdent upregulation of antioxidative enzymes: a novel pathway for proteasome inhibitor-mediated cardioprotection[J].Caidiovasc Res, 2009, 83(2): 354-361.DOI: 10.1093/cvr/cvp107.
24. Shen G, Jeong WS, Hu R, et al. Regulation of Nrf2, NF-kappaB, and AP-1 signaling pathways by chemopreventive agents[J]. Antioxid Redox Signal, 2005, 7(7): 1648-1663. DOI: 10.1089/ars.2005.7.1648.
25. Korsmeyer SJ, Shutter JR, Veis DJ, et al. Bcl-2/Bax: a rheostat that regulates an anti-oxidant pathway and cell death[J]. Semin Cancer Biol, 1993, 4: 327-32.
26. Korsmeyer SJ. Bcl-2 gene family and the regulation of programmed cell death[J]. Cancer Res, 1999, 59(7 Suppl): S1693-1700.
27. Podestà F, Romeo G, Liu WH, et al. Bax is increased in the retina of diabetic subjects and is associated with pericyte apoptosis in vivo and in vitro[J]. Am J Pathol, 2000, 156(3): 1025-1032. DOI: 10.1016/S0002-9440(10)64970-X.
28. Shen J, Wu Y, Xu JY, et al. ERK-and Akt-dependent neuroprotection by erythropoietin (EPO) against glyoxal-AGEs via modulation of Bcl-xL, Bax and BAD[J]. Invest Ophthalmol Vis Sci, 2010, 51(1): 35-46. DOI: 10.1167/iovs.09-3544.
29. Oshitari T, Yamamoto S, Hata N, et al. Mitochondria-and caspase-dependent cell death pathway involved in neuronal degeneration in diabetic retinopathy[J]. Br J Ophthalmol, 2008, 92(4): 552-556.DOI: 10.1136/bjo.2007.132308.
30. Kusner LL, Sarthy VP, Mohr S. Nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase: a role in high glucose-induced apoptosis in retinal Müller cells[J]. Invest Ophthalmol Vis Sci, 2004, 45(5): 1553-1561.
31. Mohr S, Xi X, Tang J, et al. Caspase activation in retinas of diabetic and galactosemic mice and diabetic patient[J]. Diabetes, 2002, 51(4): 1172-1179.
32. Wang L, Chen Y, Sternberg P, et al. Essential roles of the PI3 kinase/Akt pathway in regulating Nrf2-dependent antioxidant functions in the RPE[J]. Invest Ophthalmol Vis Sci, 2008, 49: 1671-1678.
33. Papaiahgari S, Zhang Q, Kleeberger SR, et al. Hyperoxia stimulates an Nrf2-ARE transcriptional response via ROS-EGFR-PI3K-Akt/ERK MAP kinase signaling in pulmonary epithelial cells[J]. Antioxid Redox Signal, 2006, 8(1-2): 43-52. DOI: 10.1089/ars.2006.8.43.
34. Zhang H, Forman HJ. Acrolein induces heme oxygenase-1 through PKC-delta and PI3K in human bronchial epithelial cells[J]. Am J Respir Cell Mol Biol, 2008, 38(4): 483-490. DOI: 10.1165/rcmb.2007-0260OC.
35. Jiang T, Chang Q, Zhao Z, et al. Melatonin-mediated cytoprotection against hyperglycemic injury in Müller cells[J/OL]. PLoS One, 2012, 7(12): 50661[2012-12-04]. https://doi.org/10.1371/journal.pone.0050661.DOI:10.1371/journal.pone.0050661.
36. Niture SK, Jaiswal AK.Nrf2 protein up-regulates antiapoptotic protein bcl-2 and prevents cellular apoptosis[J]. J Biol Chem, 2012, 287(13): 9873-9886.DOI: 10.1074/jbc.M111.312694.
37. Li S, Li J, Shen C, et al. Tert-butylhydroquinone (tBHQ) protects hepatocytes against lipotoxicity via inducing autophagy independently of Nrf2 activation[J]. Biochim Biophys Acta, 2014, 1841(1): 22-33. DOI: 10.1016/j.bbalip.2013.09.004.
38. Zhang Y, Fang Liu F, Bi X, et al. The antioxidant compound tert-butylhydroquinone activates Akt in myocardium, suppresses apoptosis and ameliorates pressure overload-induced cardiac dysfunction[J/OL]. Sci Rep, 2015, 5: 13005[2015-08-11]. https://www.nature.com/articles/srep13005.DOI: 10.1038/srep13005.

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Chinese Journal of Ocular Fundus Diseases

Effect of tert-Butylhydroquinone on the expression of nuclear factor erythroid 2-related factor 2, heme oxygenase-1 and phosphatidylinositol 3-kinase in high glucose cultured retinal Müller cells

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