Skip to main content
SpringerLink
Log in

Glutaredoxin 1 protects neurons from oxygen‐glucose deprivation/reoxygenation (OGD/R)-induced apoptosis and oxidative stress via the modulation of GSK-3β/Nrf2 signaling

  • Published:
Journal of Bioenergetics and Biomembranes Aims and scope Submit manuscript

Abstract

Increasing evidence has indicated that glutaredoxin 1 (GRX1) is a potent antioxidant protein that promotes cell survival under conditions of oxidative stress. Oxidative stress-induced neuronal injury contributes to cerebral ischemia/reperfusion injury. However, the role of GRX1-mediated antioxidant defense against neuronal damage during cerebral ischemia/reperfusion injury has not been thoroughly investigated. Thus, the objective of this study was to evaluate whether GRX1 protects neurons against oxygen-glucose deprivation/reoxygenation (OGD/R)-evoked oxidative stress injury in an in vitro model of cerebral ischemia/reperfusion injury. Our data revealed that GRX1 was induced by OGD/R treatment in neurons. Functional assays indicated that loss of GRX1 exacerbated OGD/R-induced apoptosis and the generation of reactive oxygen species (ROS), while GRX1 up-regulation protected against OGD/R-evoked neuronal injury. Further investigation revealed that GRX1 promoted the nuclear expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and enhanced transcription of the Nrf2/antioxidant response element (ARE) in GOD/R-exposed neurons. Furthermore, GRX1 promoted the activation of Nrf2/ARE associated with the modulation of glycogen synthase kinase-3β (GSK-3β). GSK-3β inhibition blocked GRX1 knockdown-mediated suppression of Nrf2 activation. Notably, the suppression of Nrf2 partially reversed GRX1-mediated anti-oxidative stress injury in OGD/R-exposed neurons. In summary, these findings indicate that GRX1 protects neurons against OGD/R-induced oxidative stress injury by enhancing Nrf2 activation via the modulation of GSK-3β. Our study suggests that GRX1 is a potential neuroprotective protein that protects against cerebral ischemia/reperfusion injury.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data availability

The data and material used to support the findings of this study are available from the corresponding author upon request.

Code availability

Not applicable.

References

  • Ahmad F, Nidadavolu P, Durgadoss L, Ravindranath V (2014) Critical cysteines in Akt1 regulate its activity and proteasomal degradation: implications for neurodegenerative diseases. Free Radic Biol Med 74:118–128

    Article  PubMed  CAS  Google Scholar 

  • Allen EM, Mieyal JJ (2012) Protein-thiol oxidation and cell death: regulatory role of glutaredoxins. Antioxid Redox Signal 17:1748–1763

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Arodin L, Miranda-Vizuete A, Swoboda P, Fernandes AP (2014) Protective effects of the thioredoxin and glutaredoxin systems in dopamine-induced cell death. Free Radic Biol Med 73:328–336

    Article  PubMed  CAS  Google Scholar 

  • Bao H, Gao M (2020) Overexpression of lemur tyrosine kinase-2 protects neurons from oxygen-glucose deprivation/reoxygenation-induced injury through reinforcement of Nrf2 signaling by modulating GSK-3beta phosphorylation. Biochem Biophys Res Commun 521:964–970

    Article  PubMed  CAS  Google Scholar 

  • Benjamin EJ, Virani SS, Callaway CW, Chamberlain AM, Chang AR, Cheng S, Chiuve SE, Cushman M, Delling FN, Deo R, de Ferranti SD, Ferguson JF, Fornage M, Gillespie C, Isasi CR, Jimenez MC, Jordan LC, Judd SE, Lackland D, Lichtman JH, Lisabeth L, Liu S, Longenecker CT, Lutsey PL, Mackey JS, Matchar DB, Matsushita K, Mussolino ME, Nasir K, O’Flaherty M, Palaniappan LP, Pandey A, Pandey DK, Reeves MJ, Ritchey MD, Rodriguez CJ, Roth GA, Rosamond WD, Sampson UKA, Satou GM, Shah SH, Spartano NL, Tirschwell DL, Tsao CW, Voeks JH, Willey JZ, Wilkins JT, Wu JH, Alger HM, Wong SS, Muntner P (2018) Heart disease and stroke statistics-2018 update: a report from the American Heart Association. Circulation 137:e67–e492

    Article  PubMed  Google Scholar 

  • Bubb KJ, Kok C, Tang O, Rasko NB, Birgisdottir AB, Hansen T, Ritchie R, Bhindi R, Reisman SA, Meyer C, Ward K, Karimi Galougahi K, Figtree GA (2017) The NRF2 activator DH404 attenuates adverse ventricular remodeling post-myocardial infarction by modifying redox signalling. Free Radic Biol Med 108:585–594

    Article  PubMed  CAS  Google Scholar 

  • Burns M, Rizvi SHM, Tsukahara Y, Pimentel DR, Luptak I, Hamburg NM, Matsui R, Bachschmid MM (2020) Role of Glutaredoxin-1 and Glutathionylation in cardiovascular diseases. Int J Mol Sci 21:6803

    Article  PubMed Central  CAS  Google Scholar 

  • Cai L, Li Y, Zhang Q, Sun H, Yan X, Hua T, Zhu Q, Xu H, Fu H (2017) Salidroside protects rat liver against ischemia/reperfusion injury by regulating the GSK-3beta/Nrf2-dependent antioxidant response and mitochondrial permeability transition. Eur J Pharmacol 806:32–42

    Article  PubMed  CAS  Google Scholar 

  • Cater MA, Materia S, Xiao Z, Wolyniec K, Ackland SM, Yap YW, Cheung NS, La Fontaine S (2014) Glutaredoxin1 protects neuronal cells from copper-induced toxicity. Biometals 27:661–672

    Article  PubMed  CAS  Google Scholar 

  • Chen X, Lv Q, Hong Y, Chen X, Cheng B, Wu T (2017) IL-1beta maintains the redox balance by regulating glutaredoxin 1 expression during oral carcinogenesis. J Oral Pathol Med 46:332–339

    Article  PubMed  CAS  Google Scholar 

  • Coghlan MP, Culbert AA, Cross DA, Corcoran SL, Yates JW, Pearce NJ, Rausch OL, Murphy GJ, Carter PS, Roxbee Cox L, Mills D, Brown MJ, Haigh D, Ward RW, Smith DG, Murray KJ, Reith AD, Holder JC (2000) Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription. Chem Biol 7:793–803

    Article  PubMed  CAS  Google Scholar 

  • Cuadrado A (2015) Structural and functional characterization of Nrf2 degradation by glycogen synthase kinase 3/beta-TrCP. Free Radic Biol Med 88:147–157

    Article  PubMed  CAS  Google Scholar 

  • Godoy JR, Oesteritz S, Hanschmann EM, Ockenga W, Ackermann W, Lillig CH (2011) Segment-specific overexpression of redoxins after renal ischemia and reperfusion: protective roles of glutaredoxin 2, peroxiredoxin 3, and peroxiredoxin 6. Free Radic Biol Med 51:552–561

    Article  PubMed  CAS  Google Scholar 

  • Golpich M, Amini E, Hemmati F, Ibrahim NM, Rahmani B, Mohamed Z, Raymond AA, Dargahi L, Ghasemi R, Ahmadiani A (2015) Glycogen synthase kinase-3 beta (GSK-3beta) signaling: Implications for Parkinson’s disease. Pharmacol Res 97:16–26

    Article  PubMed  CAS  Google Scholar 

  • Gravina SA, Mieyal JJ (1993) Thioltransferase is a specific glutathionyl mixed disulfide oxidoreductase. Biochemistry 32:3368–3376

    Article  PubMed  CAS  Google Scholar 

  • Holmgren A (1979) Glutathione-dependent synthesis of deoxyribonucleotides. Characterization of the enzymatic mechanism of Escherichia coli glutaredoxin. J Biol Chem 254:3672–3678

    Article  PubMed  CAS  Google Scholar 

  • Inadomi C, Murata H, Ihara Y, Goto S, Urata Y, Yodoi J, Kondo T, Sumikawa K (2012) Overexpression of glutaredoxin protects cardiomyocytes against nitric oxide-induced apoptosis with suppressing the S-nitrosylation of proteins and nuclear translocation of GAPDH. Biochem Biophys Res Commun 425:656–661

    Article  PubMed  CAS  Google Scholar 

  • Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K, Katoh Y, Oyake T, Hayashi N, Satoh K, Hatayama I, Yamamoto M, Nabeshima Y (1997) An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun 236:313–322

    Article  PubMed  CAS  Google Scholar 

  • Johnson WM, Wilson-Delfosse AL, Chen SG, Mieyal JJ (2015) The roles of redox enzymes in Parkinson’s disease: Focus on glutaredoxin. Ther Targets Neurol Dis 2:e790

    PubMed  PubMed Central  Google Scholar 

  • Kenchappa RS, Ravindranath V (2003) Glutaredoxin is essential for maintenance of brain mitochondrial complex I: studies with MPTP. FASEB J 17:717–719

    Article  PubMed  CAS  Google Scholar 

  • Kenchappa RS, Diwakar L, Annepu J, Ravindranath V (2004) Estrogen and neuroprotection: higher constitutive expression of glutaredoxin in female mice offers protection against MPTP-mediated neurodegeneration. FASEB J 18:1102–1104

    Article  PubMed  CAS  Google Scholar 

  • Kensler TW, Wakabayashi N, Biswal S (2007) Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol 47:89–116

    Article  PubMed  CAS  Google Scholar 

  • Lee MJ, Jin N, Grandis JR, Johnson DE (2020) Alterations and molecular targeting of the GSK-3 regulator, PI3K, in head and neck cancer. Biochim Biophys Acta Mol Cell Res 1867:118679

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lekli I, Mukherjee S, Ray D, Gurusamy N, Kim YH, Tosaki A, Engelman RM, Ho YS, Das DK (2010) Functional recovery of diabetic mouse hearts by glutaredoxin-1 gene therapy: role of Akt-FoxO-signaling network. Gene Ther 17:478–485

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Li S, Sun Y, Qi X, Shi Y, Gao H, Wu Q, Liu X, Yu H, Zhang C (2014) Protective effect and mechanism of glutaredoxin 1 on coronary arteries endothelial cells damage induced by high glucose. Biomed Mater Eng 24:3897–3903

    PubMed  Google Scholar 

  • Li Y, Ren M, Wang X, Cui X, Zhao H, Zhao C, Zhou J, Guo Y, Hu Y, Yan C, Berk B, Wang J (2017) Glutaredoxin 1 mediates the protective effect of steady laminar flow on endothelial cells against oxidative stress-induced apoptosis via inhibiting Bim. Sci Rep 7:15539

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Liu X, Jann J, Xavier C, Wu H (2015) Glutaredoxin 1 (Grx1) protects human retinal pigment epithelial cells from oxidative damage by preventing AKT glutathionylation. Invest Ophthalmol Vis Sci 56:2821–2832

    Article  PubMed  CAS  Google Scholar 

  • Liu X, Xavier C, Jann J, Wu H (2016) Salvianolic acid B (Sal B) protects retinal pigment epithelial cells from oxidative stress-induced cell death by activating Glutaredoxin 1 (Grx1). Int J Mol Sci 17:15539

    Google Scholar 

  • Liu X, Li M, Hou M, Huang W, Song J (2018) MicroRNA-135a alleviates oxygen-glucose deprivation and reoxygenation-induced injury in neurons through regulation of GSK-3beta/Nrf2 signaling. J Biochem Mol Toxicol 32:e22159

  • Lo EH, Dalkara T, Moskowitz MA (2003) Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci 4:399–415

    Article  PubMed  CAS  Google Scholar 

  • Lundberg M, Johansson C, Chandra J, Enoksson M, Jacobsson G, Ljung J, Johansson M, Holmgren A (2001) Cloning and expression of a novel human glutaredoxin (Grx2) with mitochondrial and nuclear isoforms. J Biol Chem 276:26269–26275

    Article  PubMed  CAS  Google Scholar 

  • Ma Q, He X (2012) Molecular basis of electrophilic and oxidative defense: promises and perils of Nrf2. Pharmacol Rev 64:1055–1081

    Article  PubMed  CAS  Google Scholar 

  • Madusanka RK, Tharuka MDN, Liyanage DS, Sirisena D, Lee J (2020) Role of rockfish (Sebastes schlegelii) glutaredoxin 1 in innate immunity, and alleviation of cellular oxidative stress: Insights into localization, molecular characteristics, transcription, and function. Comp Biochem Physiol B Biochem Mol Biol 243–244:110432

    Article  PubMed  CAS  Google Scholar 

  • Park SY, Choi YW, Park G (2018) Nrf2-mediated neuroprotection against oxygen-glucose deprivation/reperfusion injury by emodin via AMPK-dependent inhibition of GSK-3beta. J Pharm Pharmacol 70:525–535

    Article  PubMed  CAS  Google Scholar 

  • Qi X, Xu A, Gao Y, Shi Y, Sun X, Xu J, Liu J, Lan Q, Chang L, Zhang C, Yu H (2016) Cardiac damage and dysfunction in diabetic cardiomyopathy are ameliorated by Grx1. Genet Mol Res 15:3

    Google Scholar 

  • Rada P, Rojo AI, Evrard-Todeschi N, Innamorato NG, Cotte A, Jaworski T, Tobon-Velasco JC, Devijver H, Garcia-Mayoral MF, Van Leuven F, Hayes JD, Bertho G, Cuadrado A (2012) Structural and functional characterization of Nrf2 degradation by the glycogen synthase kinase 3/beta-TrCP axis. Mol Cell Biol 32:3486–3499

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Rana AK, Singh D (2018) Targeting glycogen synthase kinase-3 for oxidative stress and neuroinflammation: Opportunities, challenges and future directions for cerebral stroke management. Neuropharmacology 139:124–136

    Article  PubMed  CAS  Google Scholar 

  • Saito A, Maier CM, Narasimhan P, Nishi T, Song YS, Yu F, Liu J, Lee YS, Nito C, Kamada H, Dodd RL, Hsieh LB, Hassid B, Kim EE, Gonzalez M, Chan PH (2005) Oxidative stress and neuronal death/survival signaling in cerebral ischemia. Mol Neurobiol 31:105–116

    Article  PubMed  CAS  Google Scholar 

  • Silva-Islas CA, Maldonado PD (2018) Canonical and non-canonical mechanisms of Nrf2 activation. Pharmacol Res 134:92–99

    Article  PubMed  CAS  Google Scholar 

  • Singh A, Venkannagari S, Oh KH, Zhang YQ, Rohde JM, Liu L, Nimmagadda S, Sudini K, Brimacombe KR, Gajghate S, Ma J, Wang A, Xu X, Shahane SA, Xia M, Woo J, Mensah GA, Wang Z, Ferrer M, Gabrielson E, Li Z, Rastinejad F, Shen M, Boxer MB, Biswal S (2016) Small molecule inhibitor of NRF2 selectively intervenes therapeutic resistance in KEAP1-deficient NSCLC tumors. ACS Chem Biol 11:3214–3225

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sun J, Wei X, Lu Y, Cui M, Li F, Lu J, Liu Y, Zhang X (2017) Glutaredoxin 1 (GRX1) inhibits oxidative stress and apoptosis of chondrocytes by regulating CREB/HO-1 in osteoarthritis. Mol Immunol 90:211–218

    Article  PubMed  CAS  Google Scholar 

  • Wen J, Li X, Zheng S, Xiao Y (2020) Upregulation of Glutaredoxin 2 alleviates oxygen-glucose deprivation/reoxygenation-induced apoptosis and ROS production in neurons by enhancing Nrf2 signaling via modulation of GSK-3beta. Brain Res 1745:146946

    Article  PubMed  CAS  Google Scholar 

  • Yang F, Yi M, Liu Y, Wang Q, Hu Y, Deng H (2018) Glutaredoxin-1 silencing induces cell senescence via p53/p21/p16 signaling axis. J Proteome Res 17:1091–1100

    Article  PubMed  CAS  Google Scholar 

  • Yin J, Xu R, Wei J, Zhang S (2019) The protective effect of glutaredoxin 1/DJ-1/HSP70 signaling in renal tubular epithelial cells injury induced by ischemia. Life Sci 223:88–94

    Article  PubMed  CAS  Google Scholar 

  • Zhao T, Zhang-Akiyama QM (2020) Deficiency of Grx1 leads to high sensitivity of HeLaS3 cells to oxidative stress via excessive accumulation of intracellular oxidants including ROS. Free Radic Res 54:585–605

    Article  PubMed  CAS  Google Scholar 

  • Zhu J, Li X, Qi H, Gu Z, Song S, Yang X, Zhou G, Li C (2017) Oxidative and anti-oxidative status in muscle of young rats in response to six protein diets. Sci Rep 7:13184

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Anesthesiology, Affiliated Hospital of Shaanxi University of Traditional Chinese Medicine, No. 2 Weiyang West Road, Xianyang, Shaanxi Province, 712000, China

    Zhengguo Qiu, Chongzhen Duan & Rui Li

  2. Department of Surgery and Anesthesiology, Xi’an Hospital of Traditional Chinese Medicine, No. 69 Fengcheng Eight Road, Xi’an, Shaanxi Province, 710200, China

    Xu Li

  3. Department of Anesthesiology, The First Hospital of Yulin, No. 93 Yuxi Street, Yulin, Shaanxi, 719000, China

    Lifeng Han

Authors
  1. Zhengguo Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xu Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chongzhen Duan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rui Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lifeng Han
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Zhengguo Qiu designed the work, performed the experiment, and drafted the article. Xu Li performed the experiment. Chongzhen Duan collected the data. Rui Li collected the data. Lifeng Ha designed the work and reviewed the article. The authors read and approved the final manuscript.

Corresponding author

Correspondence to Lifeng Han.

Ethics declarations

Conflicts of interest

The authors declare no conflict of interest. 

Ethics approval

Not applicable. 

Consent to participate

Not applicable. 

Consent for publication

All authors have approved for the publication of this manuscript.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Qiu, Z., Li, X., Duan, C. et al. Glutaredoxin 1 protects neurons from oxygen‐glucose deprivation/reoxygenation (OGD/R)-induced apoptosis and oxidative stress via the modulation of GSK-3β/Nrf2 signaling. J Bioenerg Biomembr 53, 369–379 (2021). https://doi.org/10.1007/s10863-021-09898-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10863-021-09898-0

Keywords

Search

Navigation