Skip to main content
SpringerLink
Log in

LGR4 protects PC12 against OGD/R-induced oxidative stress and apoptosis through activation of AKT/GSK3β

  • Original Article
  • Published:
Molecular & Cellular Toxicology Aims and scope Submit manuscript

Abstract

Background

Leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) suppresses hypoxia/re-oxygenation-induced injury in hepatocytes, and protects against hepatic and myocardial ischemia/reperfusion (I/R)-induced injury. The role of LGR4 on cerebral I/R injury was investigated in this study.

Objective

Providing potential therapeutic target of cerebral I/R injury.

Results

Expression of LGR4 was reduced in OGD/R-induced PC12. Over-expression of LGR4 attenuated OGD/R-induced decrease of cell viability and increase of apoptosis. Increased levels of LDH, ROS, MDA, and MPO, as well as decreased SOD, in OGD/R-induced PC12, were restored by LGR4 over-expression. Over-expression of LGR4 counteracted with the suppressive effects of OGD/R on protein expression of AKT and GSK3β phosphorylation in PC12.

Conclusion

The protective effect of LGR4 against OGD/R-induced oxidative stress and apoptosis in PC12 was mediated by activation of AKT/GSK3β pathway.

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

Similar content being viewed by others

References

  • Bredesen DE, Rao RV, Mehlen P (2006) Cell death in the nervous system. Nature 443:796–802

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen T et al (2021) LGR4 silence aggravates ischemic injury by modulating mitochondrial function and oxidative stress via ERK signaling pathway in H9c2 cells. J Mol Histol 52:363–371

    Article  CAS  PubMed  Google Scholar 

  • Descloux C, Ginet V, Clarke P, Puyal J, Truttmann A (2015) Neuronal death after perinatal cerebral hypoxia-ischemia: focus on autophag™ mediated cell death. Int J Dev Neurosci 45:75–85

    Article  CAS  PubMed  Google Scholar 

  • Doherty L, Sanjay A (2020) LGRs in skeletal tissues: an emerging role for Wnt-associated adult stem cell markers in bone. JBMR plus 4:e10380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Forouzanfar F et al (2021) Safranal protects against ischemia-induced PC12 cell injury through inhibiting oxidative stress and apoptosis. Naunyn Schmiedebergs Arch Pharmacol 394:707–716

    Article  CAS  PubMed  Google Scholar 

  • Garcia M-I (2017) LGRs receptors as peculiar GPCRs involved in cancer. J Stem Cell Res Med 2:1–9

    Article  CAS  Google Scholar 

  • Huang C-K et al (2020) Lgr4 governs a pro-inflammatory program in macrophages to antagonize post-infarction cardiac repair. Circ Res 127:953–973

    Article  CAS  PubMed  Google Scholar 

  • Kasdorf E, Perlman JM (2013) Strategies to prevent reperfusion injury to the brain following intrapartum hypoxia–ischemia. Semin Fetal Neonatal Med 18:379–384

    Article  PubMed  Google Scholar 

  • Li C et al (2018) Edaravone attenuates neuronal apoptosis in hypoxic-ischemic brain damage rat model via suppression of TRAIL signaling pathway. Int J Biochem Cell Biol 99:169–177

    Article  CAS  PubMed  Google Scholar 

  • Li Z, Liu S, Lou J, Mulholland M, Zhang W (2019) LGR4 protects hepatocytes from injury in mouse. Am J Physiol Gastrointest Liver Physiol 316:G123–G131

    Article  CAS  PubMed  Google Scholar 

  • Liang F et al (2015) GPCR48/LGR4 promotes tumorigenesis of prostate cancer via PI3K/Akt signaling pathway. Med Oncol 32:49

    Article  PubMed  Google Scholar 

  • Liu S, Yin Y, Yu R, Li Y, Zhang W (2018) R-spondin3-LGR4 signaling protects hepatocytes against DMOG-induced hypoxia/reoxygenation injury through activating β-catenin. Biochem Biophys Res Commun 499:59–65

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu Y et al (2019) Glaucocalyxin B protects against oxygen-glucose-deprivation/reperfusion-induced neuronal injury in PC-12 cells. J Cell Biochem 120:6137–6144

    Article  CAS  PubMed  Google Scholar 

  • Mancini A et al (2020) LGR4 deficiency results in delayed puberty through impaired Wnt/β-catenin signaling. JCI Insight 5:e133434

    Article  PubMed  PubMed Central  Google Scholar 

  • Qian Y et al (2015) Maslinic acid promotes synaptogenesis and axon growth via Akt/GSK-3β activation in cerebral ischemia model. Eur J Pharmacol 764:298–305

    Article  CAS  PubMed  Google Scholar 

  • Ramon R et al (2013) Oxidative stress and pathophysiology of ischemic stroke: novel therapeutic opportunities. CNS Neurol Disord Drug Targets 12:698–714

    Article  Google Scholar 

  • Sierra C, Coca A, Schiffrin EL (2011) Vascular mechanisms in the pathogenesis of stroke. Curr Hypertens Rep 13:200–207

    Article  CAS  PubMed  Google Scholar 

  • Singla B et al (2021) Role of R-spondin 2 in arterial lymphangiogenesis and atherosclerosis. Cardiovasc Res 117:1489–1509

    Article  CAS  PubMed  Google Scholar 

  • Tan B et al (2018) Inhibition of Rspo-Lgr4 facilitates checkpoint blockade therapy by switching macrophage polarization. Can Res 78:4929

    Article  CAS  Google Scholar 

  • Tan C et al (2020) Responses of immune organs following cerebral ischemic stroke. J Nippon Med Sch 88(3):228–237

    Article  PubMed  Google Scholar 

  • Vasileva LV, Savova MS, Tews D, Wabitsch M, Georgiev MI (2021) Rosmarinic acid attenuates obesity and obesity-related inflammation in human adipocytes. Food Chem Toxicol 149:112002

    Article  CAS  PubMed  Google Scholar 

  • Wiatrak B, Kubis-Kubiak A, Piwowar A, Barg E (2020) PC12 cell line: cell types, coating of culture vessels, differentiation and other culture conditions. Cells 9:958

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang Z, Wang L, Hu Y, Wang F (2020) Butorphanol protects PC12 cells against OGD/R-induced inflammation and apoptosis. Mol Med Rep 22:1969–1975

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yao H et al (2019) Sikokianin a from Wikstroemia indica protects PC12 cells against OGD/R-induced injury via inhibiting oxidative stress and activating Nrf2. Nat Prod Res 33:3450–3453

    Article  CAS  PubMed  Google Scholar 

  • Yi J et al (2013) Analysis of LGR4 receptor distribution in human and mouse tissues. PLoS ONE 8:e78144–e78144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu Q, Dai H, Jiang Y, Zha Y, Zhang J (2021) Sevoflurane alleviates oxygen-glucose deprivation/reoxygenation-induced injury in HT22 cells through regulation of the PI3K/AKT/GSK3β signaling pathway. Exp Ther Med 21:376–376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang Z, Yang W (2021) Paeoniflorin protects PC12 cells from oxygen-glucose deprivation/reoxygenation-induced injury via activating JAK2/STAT3 signaling. Exp Ther Med 21:572–572

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang X et al (2013) Cerebral ischemia-reperfusion-induced autophagy protects against neuronal injury by mitochondrial clearance. Autophagy 9:1321–1333

    Article  CAS  PubMed  Google Scholar 

  • Zhang J, Li Q, Zhang S, Xu Q, Wang T (2016) Lgr4 promotes prostate tumorigenesis through the Jmjd2a/AR signaling pathway. Exp Cell Res 349:77–84

    Article  CAS  PubMed  Google Scholar 

  • Zhang J-F et al (2017) Parthenolide attenuates cerebral ischemia/reperfusion injury via Akt/GSK-3β pathway in PC12 cells. Biomed Pharmacother 89:1159–1165

    Article  CAS  PubMed  Google Scholar 

  • Zhao B et al (2018) GPR17 mediates ischemia-like neuronal injury via microglial activation. Int J Mol Med 42:2750–2762

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu J et al (2015) Targeted deletion of the murine Lgr4 gene decreases lens epithelial cell resistance to oxidative stress and induces age-related cataract formation. PLoS ONE 10:e0119599–e0119599

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

Not applicable.

Author information

Authors and Affiliations

  1. Department of Neurology, The Fifth Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region, Ürümqi City, 830000, China

    Jing Pei

  2. Department of Neurology, Nanjing Jiangbei Hospital, No. 552, Geguan Road, Liuhe District, Nanjing, 210044, Jiangsu, China

    Liqin Luan

Authors
  1. Jing Pei
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Liqin Luan
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JP and LL designed the study, supervised the data collection, JP analyzed the data, LL interpreted the data, prepare the manuscript for publication and reviewed the draft of the manuscript. All authors have read and approved the manuscript.

Corresponding author

Correspondence to Liqin Luan.

Ethics declarations

Conflict of interest

Jing Pei declares that she has no conflict of interest. Liqin Luan declares that she has no conflict of interest.

Ethical approval

All animal experiments were approved by the Ethics Committee of the Fifth Affiliated Hospital of Xinjiang Medical University for the use of animals and conducted in accordance with the National Institutes of Health Laboratory Animal Care and Use Guidelines.

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

Pei, J., Luan, L. LGR4 protects PC12 against OGD/R-induced oxidative stress and apoptosis through activation of AKT/GSK3β. Mol. Cell. Toxicol. 19, 33–39 (2023). https://doi.org/10.1007/s13273-021-00202-0

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13273-021-00202-0

Keywords

Search

Navigation