Skip to main content
SpringerLink
Log in

Ebselen ameliorates renal ischemia–reperfusion injury via enhancing autophagy in rats

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Renal ischemia–reperfusion (I/R) injury is one of the most common causes of chronic kidney disease (CKD). It brings unfavorable outcomes to the patients and leads to a considerable socioeconomic burden. The study of renal I/R injury is still one of the hot topics in the medical field. Ebselen is an organic selenide that attenuates I/R injury in various organs. However, its effect and related mechanism underlying renal I/R injury remains unclear. In this study, we established a rat model of renal I/R injury to study the preventive effect of ebselen on renal I/R injury and further explore the potential mechanism of its action. We found that ebselen pretreatment reduced renal dysfunction and tissue damage caused by renal I/R. In addition, ebselen enhanced autophagy and inhibited oxidative stress. Additionally, ebselen pretreatment activated the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. The protective effect of ebselen was suppressed by autophagy inhibitor wortmannin. In conclusion, ebselen could ameliorate renal I/R injury, probably by enhancing autophagy, activating the Nrf2 signaling pathway, and reducing oxidative stress.

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
Fig. 7
Fig. 8

Similar content being viewed by others

Data availability

The data used to support the findings of this study are included in the article.

Abbreviations

ARE:

Antioxidant response element

BUN:

Blood urea nitrogen

GPX:

(1 or 3) Glutathione peroxidase (1 or 3)

HO-1:

Heme oxygenase-1

I/R:

Ischemia–reperfusion

Kim-1:

Kidney injury molecule 1

Keap-1:

Kelch-like ECH-associated protein 1

LAMP1:

Lysosomal associated membrane protein 1

LC3-II:

Microtubule-associated protein 1 light chain 3-II

MDA:

Malondialdehyde

Maf:

Musculoaponeurotic fibrosarcoma oncogene

NGAL:

Neutrophil gelatinase associated lipocalin

Nox4:

Nicotinamide adenine dinucleotide phosphate oxidase 4

Nrf2:

Nuclear factor erythroid 2-related factor 2

Scr:

Serum creatinine

SOD:

Superoxide dismutase

References

  1. Bonventre JV, Yang L (2011) Cellular pathophysiology of ischemic acute kidney injury. J Clin Invest 121:4210–4221. https://doi.org/10.1172/jci45161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Mir MC, Pavan N, Parekh DJ (2016) Current paradigm for ischemia in kidney surgery. J Urol 195:1655–1663. https://doi.org/10.1016/j.juro.2015.09.099

    Article  PubMed  Google Scholar 

  3. Singh AP, Singh N, Pathak D, Bedi PMS (2019) Estradiol attenuates ischemia reperfusion-induced acute kidney injury through PPAR-γ stimulated eNOS activation in rats. Mol Cell Biochem 453:1–9. https://doi.org/10.1007/s11010-018-3427-4

    Article  CAS  PubMed  Google Scholar 

  4. Wszolek MF, Kenney PA, Libertino JA (2011) Nonclamping partial nephrectomy: towards improved nephron sparing. Nat Rev Urol 8:523–527. https://doi.org/10.1038/nrurol.2011.103

    Article  PubMed  Google Scholar 

  5. Bomer N, Grote Beverborg N, Hoes MF, Streng KW, Vermeer M, Dokter MM, IJmker J, Anker SD, Cleland JGF, Hillege HL, Lang CC, Ng LL, Samani NJ, Tromp J, van Veldhuisen DJ, Touw DJ, Voors AA, van der Meer PP (2020) Selenium and outcome in heart failure. Eur J Heart Fail 22:1415–1423. https://doi.org/10.1002/ejhf.1644

    Article  CAS  PubMed  Google Scholar 

  6. Nath KA, Paller MS (1990) Dietary deficiency of antioxidants exacerbates ischemic injury in the rat kidney. Kidney Int 38:1109–1117. https://doi.org/10.1038/ki.1990.320

    Article  CAS  PubMed  Google Scholar 

  7. Liu L, Liu C, Hou L, Lv J, Wu F, Yang X, Ren S, Ji W, Wang M, Chen L (2015) Protection against ischemia/reperfusion─induced renal injury by co─treatment with erythropoietin and sodium selenite. Mol Med Rep 12:7933–7940. https://doi.org/10.3892/mmr.2015.4426

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ostróżka-Cieślik A, Dolińska B, Ryszka F (2020) Therapeutic potential of selenium as a component of preservation solutions for kidney transplantation. Molecules. https://doi.org/10.3390/molecules25163592

    Article  PubMed  PubMed Central  Google Scholar 

  9. Zhang J, Saad R, Taylor EW, Rayman MP (2020) Selenium and selenoproteins in viral infection with potential relevance to COVID-19. Redox Biol 37:101715. https://doi.org/10.1016/j.redox.2020.101715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Noguchi N (2016) Ebselen, a useful tool for understanding cellular redox biology and a promising drug candidate for use in human diseases. Arch Biochem Biophys 595:109–112. https://doi.org/10.1016/j.abb.2015.10.024

    Article  CAS  PubMed  Google Scholar 

  11. Kil J, Lobarinas E, Spankovich C, Griffiths SK, Antonelli PJ, Lynch ED, Le Prell CG (2017) Safety and efficacy of ebselen for the prevention of noise-induced hearing loss: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 390:969–979. https://doi.org/10.1016/s0140-6736(17)31791-9

    Article  CAS  PubMed  Google Scholar 

  12. Aras M, Altaş M, Meydan S, Nacar E, Karcıoğlu M, Ulutaş KT, Serarslan Y (2014) Effects of ebselen on ischemia/reperfusion injury in rat brain. Int J Neurosci 124:771–776. https://doi.org/10.3109/00207454.2013.879581

    Article  CAS  PubMed  Google Scholar 

  13. Namura S, Nagata I, Takami S, Masayasu H, Kikuchi H (2001) Ebselen reduces cytochrome c release from mitochondria and subsequent DNA fragmentation after transient focal cerebral ischemia in mice. Stroke 32:1906–1911. https://doi.org/10.1161/01.str.32.8.1906

    Article  CAS  PubMed  Google Scholar 

  14. Kizilgun M, Poyrazoglu Y, Oztas Y, Yaman H, Cakir E, Cayci T, Akgul OE, Kurt YG, Yaren H, Kunak ZI, Macit E, Ozkan E, Taslipinar MY, Turker T, Ozcan A (2011) Beneficial effects of N-acetylcysteine and ebselen on renal ischemia/reperfusion injury. Ren Fail 33:512–517. https://doi.org/10.3109/0886022x.2011.574767

    Article  CAS  PubMed  Google Scholar 

  15. Zheng X, Xie L, Qin J, Shen H, Chen Z, Jin Y (2008) Effects of wortmannin on phosphorylation of PDK1, GSK3-beta, PTEN and expression of Skp2 mRNA after ischemia/reperfusion injury in the mouse kidney. Int Urol Nephrol 40:185–192. https://doi.org/10.1007/s11255-007-9215-9

    Article  CAS  PubMed  Google Scholar 

  16. He GQ, Chen Y, Liao HJ, Xu WM, Zhang W, He GL (2020) Associations between Huwe1 and autophagy in rat cerebral neuron oxygen─glucose deprivation and reperfusion injury. Mol Med Rep 22:5083–5094. https://doi.org/10.3892/mmr.2020.11611

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Paller MS, Hoidal JR, Ferris TF (1984) Oxygen free radicals in ischemic acute renal failure in the rat. J Clin Invest 74:1156–1164. https://doi.org/10.1172/jci111524

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Levine B, Kroemer G (2019) Biological functions of autophagy genes: a disease perspective. Cell 176:11–42. https://doi.org/10.1016/j.cell.2018.09.048

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Galluzzi L, Green DR (2019) Autophagy-independent functions of the autophagy machinery. Cell 177:1682–1699. https://doi.org/10.1016/j.cell.2019.05.026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hou J, Rao M, Zheng W, Fan J, Law BYK (2019) Advances on cell autophagy and its potential regulatory factors in renal ischemia-reperfusion injury. DNA Cell Biol 38:895–904. https://doi.org/10.1089/dna.2019.4767

    Article  CAS  PubMed  Google Scholar 

  21. Jiang M, Wei Q, Dong G, Komatsu M, Su Y, Dong Z (2012) Autophagy in proximal tubules protects against acute kidney injury. Kidney Int 82:1271–1283. https://doi.org/10.1038/ki.2012.261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Tan X, Zhu H, Tao Q, Guo L, Jiang T, Xu L, Yang R, Wei X, Wu J, Li X, Zhang JS (2018) FGF10 protects against renal ischemia/reperfusion injury by regulating autophagy and inflammatory signaling. Front Genet 9:556. https://doi.org/10.3389/fgene.2018.00556

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kaushal GP (2012) Autophagy protects proximal tubular cells from injury and apoptosis. Kidney Int 82:1250–1253. https://doi.org/10.1038/ki.2012.337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zhang YL, Zhang J, Cui LY, Yang S (2015) Autophagy activation attenuates renal ischemia-reperfusion injury in rats. Exp Biol Med (Maywood) 240:1590–1598. https://doi.org/10.1177/1535370215581306

    Article  CAS  Google Scholar 

  25. Liu S, Yang Y, Gao H, Zhou N, Wang P, Zhang Y, Zhang A, Jia Z, Huang S (2020) Trehalose attenuates renal ischemia-reperfusion injury by enhancing autophagy and inhibiting oxidative stress and inflammation. Am J Physiol Renal Physiol 318:F994-f1005. https://doi.org/10.1152/ajprenal.00568.2019

    Article  CAS  PubMed  Google Scholar 

  26. Zhang YL, Qiao SK, Wang RY, Guo XN (2018) NGAL attenuates renal ischemia/reperfusion injury through autophagy activation and apoptosis inhibition in rats. Chem Biol Interact 289:40–46. https://doi.org/10.1016/j.cbi.2018.04.018

    Article  CAS  PubMed  Google Scholar 

  27. Choi EK, Jung H, Kwak KH, Yi SJ, Lim JA, Park SH, Park JM, Kim S, Jee DL, Lim DG (2017) Inhibition of oxidative stress in renal ischemia-reperfusion injury. Anesth Analg 124:204–213. https://doi.org/10.1213/ane.0000000000001565

    Article  CAS  PubMed  Google Scholar 

  28. Liang HL, Sedlic F, Bosnjak Z, Nilakantan V (2010) SOD1 and MitoTEMPO partially prevent mitochondrial permeability transition pore opening, necrosis, and mitochondrial apoptosis after ATP depletion recovery. Free Radic Biol Med 49:1550–1560. https://doi.org/10.1016/j.freeradbiomed.2010.08.018

    Article  CAS  PubMed  Google Scholar 

  29. Rovcanin B, Medic B, Kocic G, Cebovic T, Ristic M, Prostran M (2016) Molecular dissection of renal ischemia-reperfusion: oxidative stress and cellular events. Curr Med Chem 23:1965–1980. https://doi.org/10.2174/0929867323666160112122858

    Article  CAS  PubMed  Google Scholar 

  30. Scherz-Shouval R, Elazar Z (2011) Regulation of autophagy by ROS: physiology and pathology. Trends Biochem Sci 36:30–38. https://doi.org/10.1016/j.tibs.2010.07.007

    Article  CAS  PubMed  Google Scholar 

  31. Li L, Tan J, Miao Y, Lei P, Zhang Q (2015) ROS and autophagy: interactions and molecular regulatory mechanisms. Cell Mol Neurobiol 35:615–621. https://doi.org/10.1007/s10571-015-0166-x

    Article  CAS  PubMed  Google Scholar 

  32. Underwood BR, Imarisio S, Fleming A, Rose C, Krishna G, Heard P, Quick M, Korolchuk VI, Renna M, Sarkar S, García-Arencibia M, O’Kane CJ, Murphy MP, Rubinsztein DC (2010) Antioxidants can inhibit basal autophagy and enhance neurodegeneration in models of polyglutamine disease. Hum Mol Genet 19:3413–3429. https://doi.org/10.1093/hmg/ddq253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Cao L, Xu J, Lin Y, Zhao X, Liu X, Chi Z (2009) Autophagy is upregulated in rats with status epilepticus and partly inhibited by vitamin E. Biochem Biophys Res Commun 379:949–953. https://doi.org/10.1016/j.bbrc.2008.12.178

    Article  CAS  PubMed  Google Scholar 

  34. Mason RP, Casu M, Butler N, Breda C, Campesan S, Clapp J, Green EW, Dhulkhed D, Kyriacou CP, Giorgini F (2013) Glutathione peroxidase activity is neuroprotective in models of Huntington’s disease. Nat Genet 45:1249–1254. https://doi.org/10.1038/ng.2732

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ahn CB, Je JY, Kim YS, Park SJ, Kim BI (2017) Induction of Nrf2-mediated phase II detoxifying/antioxidant enzymes in vitro by chitosan-caffeic acid against hydrogen peroxide-induced hepatotoxicity through JNK/ERK pathway. Mol Cell Biochem 424:79–86. https://doi.org/10.1007/s11010-016-2845-4

    Article  CAS  PubMed  Google Scholar 

  36. Loboda A, Damulewicz M, Pyza E, Jozkowicz A, Dulak J (2016) Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism. Cell Mol Life Sci 73:3221–3247. https://doi.org/10.1007/s00018-016-2223-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ucar BI, Ucar G, Saha S, Buttari B, Profumo E, Saso L (2021) Pharmacological protection against ischemia-reperfusion injury by regulating the Nrf2-Keap1-ARE signaling pathway. Antioxidants (Basel). https://doi.org/10.3390/antiox10060823

    Article  Google Scholar 

  38. Wang Y, Mandal AK, Son YO, Pratheeshkumar P, Wise JTF, Wang L, Zhang Z, Shi X, Chen Z (2018) Roles of ROS, Nrf2, and autophagy in cadmium-carcinogenesis and its prevention by sulforaphane. Toxicol Appl Pharmacol 353:23–30. https://doi.org/10.1016/j.taap.2018.06.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Park JS, Kang DH, Lee DH, Bae SH (2015) Fenofibrate activates Nrf2 through p62-dependent Keap1 degradation. Biochem Biophys Res Commun 465:542–547. https://doi.org/10.1016/j.bbrc.2015.08.056

    Article  CAS  PubMed  Google Scholar 

  40. Gao Y, Chu S, Zhang Z, Zuo W, Xia C, Ai Q, Luo P, Cao P, Chen N (2017) Early stage functions of mitochondrial autophagy and oxidative stress in acetaminophen-induced liver injury. J Cell Biochem 118:3130–3141. https://doi.org/10.1002/jcb.25788

    Article  CAS  PubMed  Google Scholar 

  41. Yang Y, Luo H, Hui K, Ci Y, Shi K, Chen G, Shi L, Xu C (2016) Selenite-induced autophagy antagonizes apoptosis in colorectal cancer cells in vitro and in vivo. Oncol Rep 35:1255–1264. https://doi.org/10.3892/or.2015.4484

    Article  CAS  PubMed  Google Scholar 

  42. Zang H, Qian S, Li J, Zhou Y, Zhu Q, Cui L, Meng X, Zhu G, Wang H (2020) The effect of selenium on the autophagy of macrophage infected by Staphylococcus aureus. Int Immunopharmacol 83:106406. https://doi.org/10.1016/j.intimp.2020.106406

    Article  CAS  PubMed  Google Scholar 

  43. Song GL, Chen C, Wu QY, Zhang ZH, Zheng R, Chen Y, Jia SZ, Ni JZ (2018) Selenium-enriched yeast inhibited β-amyloid production and modulated autophagy in a triple transgenic mouse model of Alzheimer’s disease. Metallomics 10:1107–1115. https://doi.org/10.1039/c8mt00041g

    Article  CAS  PubMed  Google Scholar 

  44. Olson GE, Whitin JC, Hill KE, Winfrey VP, Motley AK, Austin LM, Deal J, Cohen HJ, Burk RF (2010) Extracellular glutathione peroxidase (Gpx3) binds specifically to basement membranes of mouse renal cortex tubule cells. Am J Physiol Renal Physiol 298:F1244–F1253. https://doi.org/10.1152/ajprenal.00662.2009

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This study was sponsored by the National Natural Science Foundation of China (82160145), the Science and Technology Fund of Guizhou Health Commission [(gzwkj2021-212) and (gzwjkj2020-1-113)], and the Guizhou Science and Technology Project [QKHZC (2021)085].

Author information

Authors and Affiliations

  1. School of Medicine, Guizhou University, Guiyang, Guizhou, China

    Yikun Wu & Shuxiong Xu

  2. Department of Urology, Tongren City People’s Hospital, Tongren, Guizhou, China

    Hua Shi & Shang Song

  3. Department of Urology, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, China

    Yuangao Xu, Jun Pei, Wei Chen & Shuxiong Xu

Authors
  1. Yikun Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hua Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuangao Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jun Pei
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shang Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wei Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shuxiong Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed toward data analysis, drafting, and critically revising the paper, gave final approval of the version to be published, and agreed to be accountable for all aspects of the work.

Corresponding author

Correspondence to Shuxiong Xu.

Ethics declarations

Conflict of interest

The authors declare no conflicts of interest regarding the publication of this study.

Ethical approval

The study was approved by the Ethics Committee of Guizhou Provincial People’s Hospital and was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Informed consent

All authors have read and approved the publication of this paper.

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

Wu, Y., Shi, H., Xu, Y. et al. Ebselen ameliorates renal ischemia–reperfusion injury via enhancing autophagy in rats. Mol Cell Biochem 477, 1873–1885 (2022). https://doi.org/10.1007/s11010-022-04413-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-022-04413-4

Keywords

Search

Navigation