Skip to main content
SpringerLink
Log in

Receptor for Advanced Glycation End-Products (RAGE) Blockade Do Damage to Neuronal Survival via Disrupting Wnt/β-Catenin Signaling in Spinal Cord Injury

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Wnt signaling are recognized key factors in neuronal development, cell proliferation and axonal guidance. However, RAGE effect on wnt signaling after spinal cord injury (SCI) are poorly understood. Our study aims to explore RAGE blockade effect on wnt signaling after SCI. We constructed Allen SCI model and micro-injected with RAGE neutralizing antibody or IgG after injury. We determined β-catenin, wnt3a and its receptor frizzled-5 via Western blot. We determined β-catenin/NeuN expression at 2 weeks after SCI via immunofluorescence (IF). We found that β-catenin, wnt3a and wnt receptor frizzled5 expression were activated after SCI at 3 days after injury. However, RAGE blockade inhibit β-catenin, wnt3a and frizzled5 expression. We found that β-catenin accumulation in NeuN cells were activated after SCI via IF, however, RAGE blockade reduced β-catenin and NeuN positive cells. RAGE blockade attenuated number of survived neurons and decreased area of spared white matter around the epicenter. RAGE signaling may involved in disrupting wnt signaling to aids neuronal recovery after SCI.

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

Similar content being viewed by others

References

  1. Taguchi A, Blood DC, del Toro G, Canet A, Lee DC, Qu W, Tanji N, Lu Y, Lalla E, Fu C, Hofmann MA, Kislinger T, Ingram M, Lu A, Tanaka H, Hori O, Ogawa S, Stern DM, Schmidt AM (2000) Blockade of RAGE-amphoterin signalling suppresses tumour growth and metastases. Nature 405:354–360

    Article  PubMed  CAS  Google Scholar 

  2. van Beijnum JR, Buurman WA, Griffioen AW (2008) Convergence and amplification of toll-like receptor (TLR) and receptor for advanced glycation end products (RAGE) signaling pathways via high mobility group B1 (HMGB1). Angiogenesis 11:91–99

    Article  PubMed  CAS  Google Scholar 

  3. Huttunen HJ, Fages C, Rauvala H (1999) Receptor for advanced glycation end products (RAGE)-mediated neurite outgrowth and activation of NF-kappaB require the cytoplasmic domain of the receptor but different downstream signaling pathways. J Biol Chem 274:19919–19924

    Article  PubMed  CAS  Google Scholar 

  4. Donato R (2007) RAGE: a single receptor for several ligands and different cellular responses: the case of certain S100 proteins. Curr Mol Med 7:711–724

    Article  PubMed  CAS  Google Scholar 

  5. Hofmann MA, Drury S, Fu C, Qu W, Taguchi A, Lu Y, Avila C, Kambham N, Bierhaus A, Nawroth P, Neurath MF, Slattery T, Beach D, McClary J, Nagashima M, Morser J, Stern D, Schmidt AM (1999) RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell 97:889–901

    Article  PubMed  CAS  Google Scholar 

  6. Leclerc E, Fritz G, Vetter SW, Heizmann CW (2009) Binding of S100 proteins to RAGE: an update. Biochim Biophys Acta 1793:993–1007

    Article  PubMed  CAS  Google Scholar 

  7. Yan SS, Wu ZY, Zhang HP, Furtado G, Chen X, Yan SF, Schmidt AM, Brown C, Stern A, LaFaille J, Chess L, Stern DM, Jiang H (2003) Suppression of experimental autoimmune encephalomyelitis by selective blockade of encephalitogenic T-cell infiltration of the central nervous system. Nat Med 9:287–293

    Article  PubMed  CAS  Google Scholar 

  8. Logan CY, Nusse R (2004) The Wnt signaling pathway in development and disease. Ann Rev Cell Dev Biol 20:781–810

    Article  CAS  Google Scholar 

  9. Freese JL, Pino D, Pleasure SJ (2010) Wnt signaling in development and disease. Neurobiol Dis 38:148–153

    Article  PubMed  CAS  Google Scholar 

  10. Miyashita T, Koda M, Kitajo K, Yamazaki M, Takahashi K, Kikuchi A, Yamashita T (2009) Wnt-Ryk signaling mediates axon growth inhibition and limits functional recovery after spinal cord injury. J Neurotrauma 26:955–964

    Article  PubMed  Google Scholar 

  11. Fernandez-Martos CM, Gonzalez-Fernandez C, Gonzalez P, Maqueda A, Arenas E, Rodriguez FJ (2011) Differential expression of wnts after spinal cord contusion injury in adult rats. PloS ONE 6:e27000

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Liu Y, Wang X, Lu CC, Kerman R, Steward O, Xu XM, Zou Y (2008) Repulsive Wnt signaling inhibits axon regeneration after CNS injury. J Neurosci 28:8376–8382

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Gonzalez P, Fernandez-Martos CM, Gonzalez-Fernandez C, Arenas E, Rodriguez FJ (2012) Spatio-temporal expression pattern of frizzled receptors after contusive spinal cord injury in adult rats. PloS ONE 7:e50793

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Liu Y, Wang WM, Zhang XL, He HQ, Sun XL, Zeng H, Xu XF, Huang L, Zhu Z, Zhang L, Zhou XY, He YZ (2016) AGE/RAGE promotes the calcification of human aortic smooth muscle cells via the Wnt/beta-catenin axis. Am J Transl Res 8:4644–4656

    PubMed  PubMed Central  CAS  Google Scholar 

  15. Esposito G, Scuderi C, Lu J, Savani C, De Filippis D, Iuvone T, Steardo L Jr, Sheen V, Steardo L (2008) S100B induces tau protein hyperphosphorylation via Dickopff-1 up-regulation and disrupts the Wnt pathway in human neural stem cells. J Cell Mol Med 12:914–927

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Yao L, Zhao H, Tang H, Liang J, Liu L, Dong H, Zou F, Cai S (2016) The receptor for advanced glycation end products is required for beta-catenin stabilization in a chemical-induced asthma model. Br J Pharmacol 173:2600–2613

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Gao K, Shen Z, Yuan Y, Han D, Song C, Guo Y, Mei X (2016) Simvastatin inhibits neural cell apoptosis and promotes locomotor recovery via activation of Wnt/beta-catenin signaling pathway after spinal cord injury. J Neurochem 138:139–149

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Bai L, Mei X, Shen Z, Bi Y, Yuan Y, Guo Z, Wang H, Zhao H, Zhou Z, Wang C, Zhu K, Li G, Lv G (2017) Netrin-1 improves functional recovery through autophagy regulation by activating the AMPK/mTOR signaling pathway in rats with spinal cord injury. Sci Rep 7:42288

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Zhao H, Chen S, Gao K, Zhou Z, Wang C, Shen Z, Guo Y, Li Z, Wan Z, Liu C, Mei X (2017) Resveratrol protects against spinal cord injury by activating autophagy and inhibiting apoptosis mediated by the SIRT1/AMPK signaling pathway. Neuroscience 348:241–251

    Article  PubMed  CAS  Google Scholar 

  20. Wang H, Wang Y, Li D, Liu Z, Zhao Z, Han D, Yuan Y, Bi J, Mei X (2015) VEGF inhibits the inflammation in spinal cord injury through activation of autophagy. Biochem Biophys Res Commun 464:453–458

    Article  PubMed  CAS  Google Scholar 

  21. Wang H, Mei X, Cao Y, Liu C, Zhao Z, Guo Z, Bi Y, Shen Z, Yuan Y, Guo Y, Song C, Bai L, Wang Y, Yu D (2017) HMGB1/advanced glycation end products (RAGE) does not aggravate inflammation but promote endogenous neural stem cells differentiation in spinal cord injury. Sci Rep 7:10332

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Song C, Fang S, Lv G, Mei X (2013) Gastrodin promotes the secretion of brain-derived neurotrophic factor in the injured spinal cord. Neural Regen Res 8:1383–1389

    PubMed  PubMed Central  CAS  Google Scholar 

  23. MacDonald BT, Tamai K, He X (2009) Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell 17:9–26

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Gonzalez-Fernandez C, Fernandez-Martos CM, Shields SD, Arenas E, Javier Rodriguez F (2014) Wnts are expressed in the spinal cord of adult mice and are differentially induced after injury. J Neurotrauma 31:565–581

    Article  PubMed  PubMed Central  Google Scholar 

  25. Inestrosa NC, Arenas E (2010) Emerging roles of wnts in the adult nervous system. Nat Rev Neurosci 11:77–86

    Article  PubMed  CAS  Google Scholar 

  26. Schulte G (2010) International union of basic and clinical pharmacology. LXXX. The class frizzled receptors. Pharmacol Rev 62:632–667

    Article  PubMed  CAS  Google Scholar 

  27. Didangelos A, Puglia M, Iberl M, Sanchez-Bellot C, Roschitzki B, Bradbury EJ (2016) High-throughput proteomics reveal alarmins as amplifiers of tissue pathology and inflammation after spinal cord injury. Sci Rep 6:21607

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Brederson JD, Strakhova M, Mills C, Barlow E, Meyer A, Nimmrich V, Leddy M, Simler G, Schmidt M, Jarvis M, Lacy S (2016) A monoclonal antibody against the receptor for advanced glycation end products attenuates inflammatory and neuropathic pain in the mouse. Eur J Pain 20:607–614

    Article  PubMed  CAS  Google Scholar 

  29. Guo JD, Li L, Shi YM, Wang HD, Yuan YL, Shi XX, Hou SX (2014) Genetic ablation of receptor for advanced glycation end products promotes functional recovery in mouse model of spinal cord injury. Mol Cell Biochem 390:215–223

    Article  PubMed  CAS  Google Scholar 

  30. Chen KB, Uchida K, Nakajima H, Yayama T, Hirai T, Rodriguez Guerrero A, Kobayashi S, Ma WY, Liu SY, Zhu P, Baba H (2011) High-mobility group box-1 and its receptors contribute to proinflammatory response in the acute phase of spinal cord injury in rats. Spine 36:2122–2129

    Article  PubMed  Google Scholar 

  31. Kawabata H, Setoguchi T, Yone K, Souda M, Yoshida H, Kawahara K, Maruyama I, Komiya S (2010) High mobility group box 1 is upregulated after spinal cord injury and is associated with neuronal cell apoptosis. Spine 35:1109–1115

    Article  PubMed  Google Scholar 

  32. Dong Y, Gu Y, Huan Y, Wang Y, Liu Y, Liu M, Ding F, Gu X, Wang Y (2013) HMGB1 protein does not mediate the inflammatory response in spontaneous spinal cord regeneration: a hint for CNS regeneration. J Biol Chem 288:18204–18218

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Hori O, Brett J, Slattery T, Cao R, Zhang J, Chen JX, Nagashima M, Lundh ER, Vijay S, Nitecki D et al (1995) The receptor for advanced glycation end products (RAGE) is a cellular binding site for amphoterin. Mediation of neurite outgrowth and co-expression of rage and amphoterin in the developing nervous system. J Biol Chem 270:25752–25761

    Article  PubMed  CAS  Google Scholar 

  34. Huttunen HJ, Kuja-Panula J, Sorci G, Agneletti AL, Donato R, Rauvala H (2000) Coregulation of neurite outgrowth and cell survival by amphoterin and S100 proteins through receptor for advanced glycation end products (RAGE) activation. J Biol Chem 275:40096–40105

    Article  PubMed  CAS  Google Scholar 

  35. Perrone L, Peluso G, Melone MA (2008) RAGE recycles at the plasma membrane in S100B secretory vesicles and promotes Schwann cells morphological changes. J Cell Physiol 217:60–71

    Article  PubMed  CAS  Google Scholar 

  36. Sbai O, Devi TS, Melone MA, Feron F, Khrestchatisky M, Singh LP, Perrone L (2010) RAGE-TXNIP axis is required for S100B-promoted Schwann cell migration, fibronectin expression and cytokine secretion. J Cell Sci 123:4332–4339

    Article  PubMed  CAS  Google Scholar 

  37. Schmitt AM, Shi J, Wolf AM, Lu CC, King LA, Zou Y (2006) Wnt-Ryk signalling mediates medial-lateral retinotectal topographic mapping. Nature 439:31–37

    Article  PubMed  CAS  Google Scholar 

  38. Patel AK, Park KK, Hackam AS (2017) Wnt signaling promotes axonal regeneration following optic nerve injury in the mouse. Neuroscience 343:372–383

    Article  PubMed  CAS  Google Scholar 

  39. Yin ZS, Zu B, Chang J, Zhang H (2008) Repair effect of Wnt3a protein on the contused adult rat spinal cord. Neurol Res 30:480–486

    Article  PubMed  Google Scholar 

  40. Lambert C, Cisternas P, Inestrosa NC (2016) Role of Wnt signaling in central nervous system injury. Mol Neurobiol 53:2297–2311

    Article  PubMed  CAS  Google Scholar 

  41. Strand NS, Hoi KK, Phan TMT, Ray CA, Berndt JD, Moon RT (2016) Wnt/beta-catenin signaling promotes regeneration after adult zebrafish spinal cord injury. Biochem Biophys Res Commun 477:952–956

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (NSFC) (Nos. 81471854, 81671907). We thank the teachers from Liaoning University of Traditional Chinese Medicine, who helped in writing the manuscript and the technology support of Key Laboratory of Neurodegenerative Diseases of Liaoning Province, Jinzhou Medical University.

Author information

Authors and Affiliations

  1. Department of Orthopedic, Liaoning University of Traditional Chinese Medicine, Shenyang, People’s Republic of China

    Hongyu Wang

  2. Department of Stomatology, Second Affiliated Hospital of Jinzhou Medical University, Jinzhou, People’s Republic of China

    Ziming Zhao

  3. Department of Endocrinology, First Affiliated Hospital of Jinzhou Medical University, Jinzhou, People’s Republic of China

    Chang Liu

  4. Department of Orthopedic, First Affiliated Hospital of Jinzhou Medical University, Jinzhou, People’s Republic of China

    Zhanpeng Guo, Yajiang Yuan, Haoshen Zhao, Zipeng Zhou & Xifan Mei

  5. Liaoning University of Traditional Chinese Medicine, Shenyang, People’s Republic of China

    Xifan Mei

  6. Jinzhou Medical University, 3-40 Songpo Road, Jinzhou, 121000, People’s Republic of China

    Xifan Mei

Authors
  1. Hongyu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ziming Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhanpeng Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yajiang Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Haoshen Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Zipeng Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xifan Mei
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xifan Mei.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, H., Zhao, Z., Liu, C. et al. Receptor for Advanced Glycation End-Products (RAGE) Blockade Do Damage to Neuronal Survival via Disrupting Wnt/β-Catenin Signaling in Spinal Cord Injury. Neurochem Res 43, 1405–1412 (2018). https://doi.org/10.1007/s11064-018-2555-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-018-2555-2

Keywords

Search

Navigation