Abstract
Glaucoma is a chronic optic neuropathy that could lead to permanent vision loss. Primary open-angle glaucoma (POAG) is the most common type of glaucoma, with elevated intraocular pressure (IOP) as a major risk factor. IOP is mainly regulated by trabecular meshwork (TM), an important component of the conventional aqueous humor (AH) outflow pathway. TM cells are constantly subjected to oxidative stress. Long-term exposure to oxidative stress has been shown to cause elevation of AH outflow resistance, leading to higher IOP. In this study, we induced chronic oxidative stress in human trabecular meshwork (TM-1) cells with 1 μM rotenone and investigated the levels of reactive oxygen species (ROS), autophagy, and mitochondrial functions. Protective effects of rapamycin, an inducer of autophagy, were also investigated. Our data indicated that rotenone significantly increased oxidative stress, but not autophagy, in TM-1 cells. Rapamycin at 10 nM effectively suppressed the rotenone-induced cell apoptosis, as well as the ROS elevation. The protective effects of rapamycin could be associated to the induction of autophagy and removal of damaged mitochondria in TM-1 cells. Our results suggest autophagy has important roles in protecting TM-1 cells from oxidative stress, which could be further developed into a novel treatment to POAG.
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References
Jonas JB, Aung T, Bourne RR, Bron AM, Ritch R, Panda-Jonas S (2017) Glaucoma. Lancet 390(10108):2183–2193. https://doi.org/10.1016/S0140-6736(17)31469-1
Bourne RR, Taylor HR, Flaxman SR, Keeffe J, Leasher J, Naidoo K, Pesudovs K, White RA et al (2016) Number of people blind or visually impaired by glaucoma worldwide and in world regions 1990–2010: a meta-analysis. PLoS One 11(10):e0162229. https://doi.org/10.1371/journal.pone.0162229
Leske MC, Heijl A, Hussein M, Bengtsson B, Hyman L, Komaroff E, Early Manifest Glaucoma Trial G (2003) Factors for glaucoma progression and the effect of treatment: the early manifest glaucoma trial. Arch Ophthalmol 121(1):48–56
Llobet A, Gasull X, Gual A (2003) Understanding trabecular meshwork physiology: a key to the control of intraocular pressure? News Physiol Sci 18:205–209
Liton PB (2016) The autophagic lysosomal system in outflow pathway physiology and pathophysiology. Exp Eye Res 144:29–37. https://doi.org/10.1016/j.exer.2015.07.013
Schieber M, Chandel NS (2014) ROS function in redox signaling and oxidative stress. Curr Biol 24(10):R453–R462
Zhang H, Kong X, Kang J, Su J, Li Y, Zhong J, Sun L (2009) Oxidative stress induces parallel autophagy and mitochondria dysfunction in human glioma U251 cells. Toxicol Sci 110(2):376–388
Porter K, Hirt J, Stamer WD, Liton PB (2015) Autophagic dysregulation in glaucomatous trabecular meshwork cells. Biochim Biophys Acta 1852(3):379–385. https://doi.org/10.1016/j.bbadis.2014.11.021
Su W, Li Z, Jia Y, Zhuo Y (2014) Rapamycin is neuroprotective in a rat chronic hypertensive glaucoma model. PLoS One 9(6):e99719. https://doi.org/10.1371/journal.pone.0099719
Del Olmo Aguado S, Núñez Älvarez C, Osborne N (2014) Rapamycin down-regulates REDD1 to blunt cell death: a potential way to maintain retinal ganglion cell function as in glaucoma. Acta Ophthalmol 92(s253):0–0
Kim J, Park DY, Bae H, Park DY, Kim D, Lee CK, Song S, Chung TY et al (2017) Impaired angiopoietin/Tie2 signaling compromises Schlemm’s canal integrity and induces glaucoma. J Clin Invest 127(10):3877–3896. https://doi.org/10.1172/JCI94668
Maurya N, Agarwal NR, Ghosh I (2016) Low-dose rotenone exposure induces early senescence leading to late apoptotic signaling cascade in human trabecular meshwork (HTM) cell line: an in vitro glaucoma model. Cell Biol Int 40(1):107–120. https://doi.org/10.1002/cbin.10561
Polansky JR, Weinreb RN, Baxter JD, Alvarado J (1979) Human trabecular cells. I. Establishment in tissue culture and growth characteristics. Invest Ophthalmol Vis Sci 18(10):1043–1049
Filla MS, Liu X, Nguyen TD, Polansky JR, Brandt CR, Kaufman PL, Peters DM (2002) In vitro localization of TIGR/MYOC in trabecular meshwork extracellular matrix and binding to fibronectin. Invest Ophthalmol Vis Sci 43(1):151–161
Keller KE, Bhattacharya SK, Borrás T, Brunner TM, Chansangpetch S, Clark AF, Dismuke WM, Du Y et al (2018) Consensus recommendations for trabecular meshwork cell isolation, characterization and culture. Exp Eye Res 171:164–173
Aparicio IM, Espino J, Bejarano I, Gallardo-Soler A, Campo ML, Salido GM, Pariente JA, Pena FJ et al (2016) Autophagy-related proteins are functionally active in human spermatozoa and may be involved in the regulation of cell survival and motility. Sci Rep 6:33647. https://doi.org/10.1038/srep33647
Kannan K, Jain SK (2000) Oxidative stress and apoptosis. Pathophysiology: the official journal of the International Society for Pathophysiology 7(3):153–163
Lee J, Giordano S, Zhang J (2012) Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling. Biochem J 441(2):523–540. https://doi.org/10.1042/BJ20111451
Davies KJ (1995) Oxidative stress: the paradox of aerobic life. In: Biochemical Society Symposia. Portland Press Limited, pp 1–31
Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J (2007) Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 39(1):44–84. https://doi.org/10.1016/j.biocel.2006.07.001
Veal EA, Day AM, Morgan BA (2007) Hydrogen peroxide sensing and signaling. Mol Cell 26(1):1–14. https://doi.org/10.1016/j.molcel.2007.03.016
Testa CM, Sherer TB, Greenamyre JT (2005) Rotenone induces oxidative stress and dopaminergic neuron damage in organotypic substantia nigra cultures. Brain Res Mol Brain Res 134(1):109–118. https://doi.org/10.1016/j.molbrainres.2004.11.007
Takeuchi H, Yanagida T, Inden M, Takata K, Kitamura Y, Yamakawa K, Sawada H, Izumi Y et al (2009) Nicotinic receptor stimulation protects nigral dopaminergic neurons in rotenone-induced Parkinson’s disease models. J Neurosci Res 87(2):576–585
Feng Y, Liang Z-H, Wang T, Qiao X, Liu H-J, Sun S-G (2006) Alpha-Synuclein redistributed and aggregated in rotenone-induced Parkinson’s disease rats. Neurosci Bull 22(5):288–293
He Y, Leung KW, Zhang YH, Duan S, Zhong XF, Jiang RZ, Peng Z, Tombran-Tink J et al (2008) Mitochondrial complex I defect induces ROS release and degeneration in trabecular meshwork cells of POAG patients: protection by antioxidants. Invest Ophthalmol Vis Sci 49(4):1447–1458. https://doi.org/10.1167/iovs.07-1361
Yu M, Sun J, Peng W, Chen Z, Lin X, Liu X, Li M, Wu K (2010) Protein expression in human trabecular meshwork: downregulation of RhoGDI by dexamethasone in vitro. Mol Vis 16:213–223
Chen M, Liu B, Gao Q, Zhuo Y, Ge J (2011) Mitochondria-targeted peptide MTP-131 alleviates mitochondrial dysfunction and oxidative damage in human trabecular meshwork cells. Invest Ophthalmol Vis Sci 52(10):7027–7037. https://doi.org/10.1167/iovs.11-7524
Yang X, Liu B, Bai Y, Chen M, Li Y, Chen M, Wei Y, Ge J et al (2011) Elevated pressure downregulates ZO-1 expression and disrupts cytoskeleton and focal adhesion in human trabecular meshwork cells. Mol Vis 17:2978–2985
Qiu X, Wu K, Lin X, Liu Q, Ye Y, Yu M (2015) Dexamethasone increases Cdc42 expression in human TM-1 cells. Curr Eye Res 40(3):290–299. https://doi.org/10.3109/02713683.2014.922191
Sies H (1997) Oxidative stress: oxidants and antioxidants. Exp Physiol 82(2):291–295
Shin YJ, Cho DY, Chung TY, Han SB, Hyon JY, Wee WR (2011) Rapamycin reduces reactive oxygen species in cultured human corneal endothelial cells. Curr Eye Res 36(12):1116–1122. https://doi.org/10.3109/02713683.2011.614372
Singh AK, Singh S, Garg G, Rizvi SI (2016) Rapamycin alleviates oxidative stress-induced damage in rat erythrocytes. Biochem Cell Biol = Biochimie et biologie cellulaire 94(5):471–479. https://doi.org/10.1139/bcb-2016-0048
Vezina C, Kudelski A, Sehgal S (1975) Rapamycin (AY-22, 989), a new antifungal antibiotic. J Antibiot 28(10):721–726
Brown EJ, Albers MW, Shin TB, Ichikawa K, Keith CT, Lane WS, Schreiber SL (1994) A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 369(6483):756–758. https://doi.org/10.1038/369756a0
Mizushima N (2010) The role of the Atg1/ULK1 complex in autophagy regulation. Curr Opin Cell Biol 22(2):132–139
Hosokawa N, Hara T, Kaizuka T, Kishi C, Takamura A, Miura Y, Iemura S-i, Natsume T et al (2009) Nutrient-dependent mTORC1 association with the ULK1–Atg13–FIP200 complex required for autophagy. Mol Biol Cell 20(7):1981–1991
Kim J, Kundu M, Viollet B, Guan K-L (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13(2):132–141
Rezaie T, Child A, Hitchings R, Brice G, Miller L, Coca-Prados M, Héon E, Krupin T et al (2002) Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science 295(5557):1077–1079
Wild P, Farhan H, McEwan DG, Wagner S, Rogov VV, Brady NR, Richter B, Korac J et al (2011) Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science 333(6039):228–233
Youle RJ, Narendra DP (2011) Mechanisms of mitophagy. Nat Rev Mol Cell Biol 12(1):9–14
Funding
This work was supported by the National Natural Science Foundation of China (to S.D.Z., 81100661), the Natural Science Foundation of Liaoning Province (to S.D.Z., 2015020560), and the Endowment Fund for Lim Por-Yen Eye Genetics Research Centre, Hong Kong.
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S.D.Z., J.N.H., C.P.P. and W.K.C. designed research; J.N.H. and W.K.C. performed research; All authors analyzed data; J.N.H., S.D.Z., C.P.P. and W.K.C. wrote the manuscript; and C.P.P. and W.K.C. supervised the project.
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He, J.N., Zhang, S.D., Qu, Y. et al. Rapamycin Removes Damaged Mitochondria and Protects Human Trabecular Meshwork (TM-1) Cells from Chronic Oxidative Stress. Mol Neurobiol 56, 6586–6593 (2019). https://doi.org/10.1007/s12035-019-1559-5
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DOI: https://doi.org/10.1007/s12035-019-1559-5