Selenomethionine (Se-Met) Induces the Cystine/Glutamate Exchanger SLC7A11 in Cultured Human Retinal Pigment Epithelial (RPE) Cells: Implications for Antioxidant Therapy in Aging Retina

Oxidative damage has been identified as a major causative factor in degenerative diseases of the retina; retinal pigment epithelial (RPE) cells are at high risk. Hence, identifying novel strategies for increasing the antioxidant capacity of RPE cells, the purpose of this study, is important. Specifically, we evaluated the influence of selenium in the form of selenomethionine (Se-Met) in cultured RPE cells on system xc- expression and functional activity and on cellular levels of glutathione, a major cellular antioxidant. ARPE-19 and mouse RPE cells were cultured with and without selenomethionine (Se-Met), the principal form of selenium in the diet. Promoter activity assay, uptake assay, RT-PCR, northern and western blots, and immunofluorescence were used to analyze the expression of xc-, Nrf2, and its target genes. Se-Met activated Nrf2 and induced the expression and function of xc- in RPE. Other target genes of Nrf2 were also induced. System xc- consists of two subunits, and Se-Met induced the subunit responsible for transport activity (SLC7A11). Selenocysteine also induced xc- but with less potency. The effect of Se-met on xc- was associated with an increase in maximal velocity and an increase in substrate affinity. Se-Met increased the cellular levels of glutathione in the control, an oxidatively stressed RPE. The Se-Met effect was selective; under identical conditions, taurine transport was not affected and Na+-coupled glutamate transport was inhibited. This study demonstrates that Se-Met enhances the antioxidant capacity of RPE by inducing the transporter xc- with a consequent increase in glutathione.

[1]  S. Z. Scalinci,et al.  Expression of Pro-Angiogenic Markers Is Enhanced by Blue Light in Human RPE Cells , 2020, Antioxidants.

[2]  S. Rowan,et al.  Glyoxalase System as a Therapeutic Target against Diabetic Retinopathy , 2020, Antioxidants.

[3]  P. Donaldson,et al.  Identification, Expression, and Roles of the Cystine/Glutamate Antiporter in Ocular Tissues , 2020, Oxidative medicine and cellular longevity.

[4]  C. Rinaldi,et al.  Effects of A2E-Induced Oxidative Stress on Retinal Epithelial Cells: New Insights on Differential Gene Response and Retinal Dystrophies , 2020, Antioxidants.

[5]  P. Roca,et al.  Micronutrients Selenomethionine and Selenocysteine Modulate the Redox Status of MCF-7 Breast Cancer Cells , 2020, Nutrients.

[6]  J. Bernatonienė,et al.  Selenium Anticancer Properties and Impact on Cellular Redox Status , 2020, Antioxidants.

[7]  I. Bellezza.  Oxidative Stress in Age-Related Macular Degeneration: Nrf2 as Therapeutic Target , 2018, Front. Pharmacol..

[8]  A. Fernandes,et al.  Organic selenium compounds as potential chemotherapeutic agents for improved cancer treatment , 2018, Free radical biology & medicine.

[9]  Yingfeng Zheng,et al.  Glutathione depletion induces ferroptosis, autophagy, and premature cell senescence in retinal pigment epithelial cells , 2018, Cell Death & Disease.

[10]  M. Bartoli,et al.  Loss of NAMPT in aging retinal pigment epithelium reduces NAD+ availability and promotes cellular senescence , 2018, Aging.

[11]  I. Pang,et al.  Involvement of Nrf2 in Ocular Diseases , 2017, Oxidative medicine and cellular longevity.

[12]  D. Gutsaeva,et al.  Oral Monomethyl Fumarate Therapy Ameliorates Retinopathy in a Humanized Mouse Model of Sickle Cell Disease. , 2016, Antioxidants & redox signaling.

[13]  Meng-Chen Lu,et al.  The Keap1–Nrf2–ARE Pathway As a Potential Preventive and Therapeutic Target: An Update , 2016, Medicinal research reviews.

[14]  N. Raddatz,et al.  Regulation of System x c − by Pharmacological Manipulation of Cellular Thiols , 2015, Oxidative medicine and cellular longevity.

[15]  E. Habib,et al.  Expression of xCT and activity of system xc− are regulated by NRF2 in human breast cancer cells in response to oxidative stress , 2015, Redox biology.

[16]  K. Bućan,et al.  Association of Age-Related Macular Degeneration with Erythrocyte Antioxidant Enzymes Activity and Serum Total Antioxidant Status , 2015, Oxidative medicine and cellular longevity.

[17]  H. Akşit,et al.  The protective effect of selenium in cisplatin-related retinotoxicity , 2014, Cutaneous and ocular toxicology.

[18]  B. Gao,et al.  Role of the Nrf2 signaling system in health and disease , 2014, Clinical genetics.

[19]  V. Gladyshev,et al.  Selenoproteins: molecular pathways and physiological roles. , 2014, Physiological reviews.

[20]  B. Yaspan,et al.  Mechanisms of age‐related macular degeneration and therapeutic opportunities , 2014, The Journal of pathology.

[21]  K. Kaarniranta,et al.  Role of antioxidant enzymes and small molecular weight antioxidants in the pathogenesis of age-related macular degeneration (AMD) , 2013, Biogerontology.

[22]  Holly L. Nicastro,et al.  Selenium and Prostate Cancer Prevention: Insights from the Selenium and Vitamin E Cancer Prevention Trial (SELECT) , 2013, Nutrients.

[23]  P. Kalivas,et al.  The cystine/glutamate antiporter system x(c)(-) in health and disease: from molecular mechanisms to novel therapeutic opportunities. , 2013, Antioxidants & redox signaling.

[24]  Amitha Domalpally,et al.  The Age-Related Eye Disease Study 2 (AREDS2): study design and baseline characteristics (AREDS2 report number 1). , 2012, Ophthalmology.

[25]  M. Davies,et al.  Photo-oxidation-induced inactivation of the selenium-containing protective enzymes thioredoxin reductase and glutathione peroxidase. , 2012, Free radical biology & medicine.

[26]  W. Hauswirth,et al.  ERK1/2 activation is a therapeutic target in age-related macular degeneration , 2012, Proceedings of the National Academy of Sciences.

[27]  J. Ambati,et al.  Mechanisms of Age-Related Macular Degeneration , 2012, Neuron.

[28]  S. Piccirillo,et al.  p38(MAPK) and ERK1/2 dictate cell death/survival response to different pro-oxidant stimuli via p53 and Nrf2 in neuroblastoma cells SH-SY5Y. , 2012, Biochemical pharmacology.

[29]  Julian J. Nussbaum,et al.  GPR109A as an anti-inflammatory receptor in retinal pigment epithelial cells and its relevance to diabetic retinopathy. , 2012, Investigative ophthalmology & visual science.

[30]  R. Bridges,et al.  System xc‐ cystine/glutamate antiporter: an update on molecular pharmacology and roles within the CNS , 2012, British journal of pharmacology.

[31]  Marc Birringer,et al.  Comparison of different selenocompounds with respect to nutritional value vs. toxicity using liver cells in culture. , 2011, The Journal of nutritional biochemistry.

[32]  D. Hicks,et al.  The retinal pigment epithelium in health and disease. , 2010, Current molecular medicine.

[33]  W. Fawzi,et al.  Role of selenium in HIV infection. , 2010, Nutrition reviews.

[34]  L. Sheck,et al.  Selenium and ocular health in New Zealand. , 2010, The New Zealand medical journal.

[35]  W. Schaffner,et al.  Acute selenium toxicity associated with a dietary supplement. , 2010, Archives of internal medicine.

[36]  V. Ganapathy,et al.  Absence of iron-regulatory protein Hfe results in hyperproliferation of retinal pigment epithelium: role of cystine/glutamate exchanger. , 2009, The Biochemical journal.

[37]  G. Cresci,et al.  Expression and localization of GPR109A (PUMA-G/HM74A) mRNA and protein in mammalian retinal pigment epithelium , 2009, Molecular vision.

[38]  V. Ganapathy,et al.  Effects of hyperglycemia and oxidative stress on the glutamate transporters GLAST and system xc− in mouse retinal Müller glial cells , 2009, Cell and Tissue Research.

[39]  S. Reddy,et al.  Genetic disruption of the Nrf2 compromises cell-cycle progression by impairing GSH-induced redox signaling , 2008, Oncogene.

[40]  W. Markesbery,et al.  Seleno-L-methionine protects against beta-amyloid and iron/hydrogen peroxide-mediated neuron death. , 2007, Antioxidants & redox signaling.

[41]  V. Ganapathy,et al.  c/ebpδ Null Mouse as a Model for the Double Knock-out of slc5a8 and slc5a12 in Kidney* , 2006, Journal of Biological Chemistry.

[42]  R. Issels,et al.  The cystine/cysteine cycle: a redox cycle regulating susceptibility versus resistance to cell death , 2006, Oncogene.

[43]  V. Ganapathy,et al.  Expression of the cystine-glutamate exchanger (xc−) in retinal ganglion cells and regulation by nitric oxide and oxidative stress , 2006, Cell and Tissue Research.

[44]  Elena Ganea,et al.  Glutathione-Related Enzymes and the Eye , 2006, Current eye research.

[45]  Hideyo Sato,et al.  Transcriptional control of cystine/glutamate transporter gene by amino acid deprivation. , 2004, Biochemical and biophysical research communications.

[46]  V. Ganapathy,et al.  Induction of cystine-glutamate transporter xc- by human immunodeficiency virus type 1 transactivator protein tat in retinal pigment epithelium. , 2004, Investigative ophthalmology & visual science.

[47]  H. Tähti,et al.  Expression of glutamate transporter subtypes in cultured retinal pigment epithelial and retinoblastoma cells , 2004, Current eye research.

[48]  G. Ghirlanda,et al.  Potential Therapeutic Effect of Antioxidants in Experimental Diabetic Retina: A Comparison between Chronic Taurine and Vitamin E Plus Selenium Supplementations , 2003, Free radical research.

[49]  Y. Seo,et al.  Selenomethionine regulation of p53 by a ref1-dependent redox mechanism , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[50]  J. Lombardini,et al.  Taurine: Evidence of Physiological Function in the Retina , 2002, Nutritional neuroscience.

[51]  Dean P. Jones,et al.  Oxidative damage and protection of the RPE , 2000, Progress in Retinal and Eye Research.

[52]  K. Head.  Natural therapies for ocular disorders, part one: diseases of the retina. , 1999, Alternative medicine review : a journal of clinical therapeutic.

[53]  S. Plafker,et al.  Mechanisms for countering oxidative stress and damage in retinal pigment epithelium. , 2012, International review of cell and molecular biology.

[54]  Emily Y. Chew,et al.  The Age-related Eye Disease Study 2 ( AREDS 2 ) Study Design and Baseline Characteristics ( AREDS 2 Report , 2012 .

[55]  G. Schrauzer,et al.  Selenium and Alzheimer's disease: a systematic review. , 2011, Journal of Alzheimer's disease : JAD.

[56]  M. Mccarty,et al.  The putative therapeutic value of high-dose selenium in proliferative retinopathies may reflect down-regulation of VEGF production by the hypoxic retina. , 2005, Medical hypotheses.

[57]  Leopold Flohé,et al.  Selenium, selenoproteins and vision. , 2005, Developments in ophthalmology.

[58]  V. Ganapathy,et al.  Structure, function, and regulation of human cystine/glutamate transporter in retinal pigment epithelial cells. , 2001, Investigative ophthalmology & visual science.

[59]  Jennifer I. Lim,et al.  A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. , 2001, Archives of ophthalmology.

[60]  H. Lane,et al.  Effect of chemical form of selenium on tissue glutathione peroxidase activity in developing rats. , 1991, The Journal of nutrition.

[61]  H. Ripps,et al.  The Review: Taurine: a " Very Essential " Amino Acid , 2022 .