Skip to main content

Advertisement

SpringerLink
Log in

Berberine protects renal tubular cells against hypoxia/reoxygenation injury via the Sirt1/p53 pathway

  • Original Paper
  • Published:
Journal of Natural Medicines Aims and scope Submit manuscript

Abstract

Berberine (BBR) has been demonstrated to protect against renal ischemia/reperfusion injury; however, the underlying molecular mechanism is largely unknown. In the present study, we examined the role of silent information regulator 1 (Sirt1)/p53 in the protective effect of BBR on hypoxia/reoxygenation (H/R)-mediated mitochondrial dysfunction in rat renal tubular epithelial cells (NRK-52E cells). NRK-52E cells were preconditioned with small interfering RNA targeting Sirt1 (Sirt1-siRNA) and BBR before subjected to H/R. Cell damage was assessed by CCK8 assay and detection of oxidative parameters. The apoptotic rate was determined by flow cytometry and Hoechst 33258 staining. The expression of apoptotic markers, Sirt1, p53 and the translocation of p53 were examined by Western blotting assay. Nuclear p53 deacetylation by Sirt1 was detected using immunoprecipitation. Compared with the H/R group, BBR pretreatment increased cell viability and inhibited mitochondrial oxidative stress and apoptosis. Protein expression of Sirt1 was also enhanced along with a reduction of p53. Furthermore, both nuclear translocation of p53 and its acetylation were inhibited in NRK-52E cells pretreated with BBR. However, the knockdown of Sirt1 counteracted the renoprotection of BBR. BBR preconditioning protects rat renal tubular epithelial cells against H/R-induced mitochondrial dysfunction via regulating the Sirt1/p53 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

Similar content being viewed by others

References

  1. Ponticelli C (2014) Ischaemia-reperfusion injury: a major protagonist in kidney transplantation. Nephrol Dial Transplant 29:1134–1140

    Article  CAS  Google Scholar 

  2. Salvadori M, Rosso G, Bertoni E (2015) Update on ischemia-reperfusion injury in kidney transplantation: pathogenesis and treatment. World J Transplant 5:52–67

    Article  Google Scholar 

  3. Kezic A, Spasojevic I, Lezaic V, Bajcetic M (2016) Mitochondria-targeted antioxidants: future perspectives in kidney ischemia reperfusion injury. Oxid Med Cell Longev 2016:2950503

    Article  Google Scholar 

  4. Chatauret N, Badet L, Barrou B, Hauet T (2014) Ischemia-reperfusion: from cell biology to acute kidney injury. Prog Urol 1:S4–S12

    Article  Google Scholar 

  5. Guan Y, Hao CM (2016) SIRT1 and kidney function. Kidney Dis (Basel) 1:258–265

    Article  Google Scholar 

  6. Kumar A, Chauhan S (2016) How much successful are the medicinal chemists in modulation of SIRT1: a critical review. Eur J Med Chem 119:45–69

    Article  CAS  Google Scholar 

  7. Van Leeuwen I, Lain S (2009) Sirtuins and p53. Adv Cancer Res 102:171–195

    Article  Google Scholar 

  8. Nakamura K, Zhang M, Kageyama S, Ke B, Fujii T, Sosa RA, Reed EF, Datta N, Zarrinpar A, Busuttil RW, Araujo JA, Kupiec-Weglinski JW (2017) Macrophage heme oxygenase-1-SIRT1-p53 axis regulates sterile inflammation in liver ischemia- reperfusion injury. J Hepatol 67:1232–1242

    Article  CAS  Google Scholar 

  9. Hsu CP, Zhai P, Yamamoto T, Maejima Y, Matsushima S, Hariharan N, Shao D, Takagi H, Oka S, Sadoshima J (2010) Silent information regulator 1 protects the heart from ischemia/reperfusion. Circulation 122:2170–2182

    Article  Google Scholar 

  10. He W, Wang Y, Zhang MZ, You L, Davis LS, Fan H, Yang HC, Fogo AB, Zent R, Harris RC, Breyer MD, Hao CM (2010) Sirt1 activation protects the mouse renal medulla from oxidative injury. J Clin Invest 120:1056–1068

    Article  CAS  Google Scholar 

  11. Ying Y, Kim J, Westphal SN, Long KE, Padanilam BJ (2014) Targeted deletion of p53 in the proximal tubule prevents ischemic renal injury. J Am Soc Nephrol 25:2707–2716

    Article  CAS  Google Scholar 

  12. Cicero AF, Baggioni A (2016) Berberine and its role in chronic disease. Adv Exp Med Biol 928:27–45

    Article  CAS  Google Scholar 

  13. Jin Y, Khadka DB, Cho WJ (2016) Pharmacological effects of berberine and its derivatives: a patent update. Expert Opin Ther Pat 26:229–243

    Article  CAS  Google Scholar 

  14. Kumar A, Ekavali, Chopra K, Mukherjee M, Pottabathini R, Dhull DK (2015) Current knowledge and pharmacological profile of berberine: an update. Eur J Pharmacol 761:288–297

    Article  CAS  Google Scholar 

  15. Lin Y, Sheng M, Weng Y, Xu R, Lu N, Du H, Yu W (2017) Berberine protects against ischemia/reperfusion injury after orthotopic liver transplantation via activating Sirt1/FoxO3α induced autophagy. Biochem Biophys Res Commun 483:885–891

    Article  CAS  Google Scholar 

  16. Yu W, Sheng M, Xu R, Yu J, Cui K, Tong J, Shi L, Ren H, Du H (2013) Berberine protects human renal proximal tubular cells from hypoxia/reoxygenation injury via inhibiting endoplasmic reticulum and mitochondrial stress pathways. J Transl Med 11(1):24

    Article  CAS  Google Scholar 

  17. Gomes AP, Duarte FV, Nunes P, Hubbard BP, Teodoro JS, Varela AT, Jones JG, Sinclair DA, Palmeira CM, Rolo AP (1822) Berberine protects against high fat diet-induced dysfunction in muscle mitochondria by inducing SIRT1-dependent mitochondrial biogenesis. Biochim Biophys Acta 2012:185–195

    Google Scholar 

  18. Zhang H, Shan Y, Wu Y, Xu C, Yu X, Zhao J, Yan J, Shang W (2017) Berberine suppresses LPS-induced inflammation through modulating Sirt1/NF-κB signaling pathway in RAW264.7 cells. Int Immunopharmacol 52:93–100

    Article  CAS  Google Scholar 

  19. Laptenko O, Prives C (2017) P53: master of life, death, and the epigenome. Genes Dev 31:955–956

    Article  CAS  Google Scholar 

  20. Gu B, Zhu WG (2012) Surf the post-translational modification network of p53 regulation. Int J Biol Sci 8:672–684

    Article  Google Scholar 

  21. Reed SM, Quelle DE (2014) p53 acetylation: regulation and consequences. Cancers (Basel) 7:30–69

    Article  Google Scholar 

  22. Kim DH, Jung YJ, Lee JE, Lee AS, Kang KP, Lee S, Park SK, Han MK, Lee SY, Ramkumar KM, Sung MJ, Kim W (2011) SIRT1 activation by resveratrol ameliorates cisplatin-induced renal injury through deacetylation of p53. Am J Physiol Renal Physiol 301:F427–F435

    Article  CAS  Google Scholar 

  23. Hao J, Wei Q, Mei S, Li L, Su Y, Mei C, Dong Z (2017) Induction of microRNA-17-5p by p53 protects against renal ischemia-reperfusion injury by targeting death receptor 6. Kidney Int 91:106–118

    Article  CAS  Google Scholar 

  24. Park GB, Park SH, Kim D, Kim YS, Yoon SH, Hur DY (2016) Berberine induces mitochondrial apoptosis of EBV-transformed B cells through p53-mediated regulation of XAF1 and GADD45α. Int J Oncol 49:411–421

    Article  CAS  Google Scholar 

  25. Wang N, Zhu M, Wang X, Tan HY, Tsao SW, Feng Y (1839) Berberine-induced tumor suppressor p53 up-regulation gets involved in the regulatory network of MIR-23a in hepatocellular carcinoma. Biochim Biophys Acta 2014:849–857

    Google Scholar 

  26. Qin W, Xie W, Yang X, Xia N, Yang K (2016) Inhibiting microRNA-449 attenuates cisplatin-induced injury in NRK-52E cells possibly via regulating the SIRT1/P53/BAX pathway. Med Sci Monit 22:818–823

    Article  CAS  Google Scholar 

  27. Gao R, Chen J, Hu Y, Li Z, Wang S, Shetty S, Fu J (2014) Sirt1 deletion leads to enhanced inflammation and aggravates endotoxin-induced acute kidney injury. PLoS One 9:e98909

    Article  Google Scholar 

  28. Yu J, Zhang L (2003) No PUMA, no death: implications for p53-dependent apoptosis. Cancer Cell 4:248–249

    Article  CAS  Google Scholar 

  29. Jiang M, Wei Q, Wang J, Du Q, Yu J, Zhang L, Dong Z (2006) Regulation of PUMA-alpha by p53 in cisplatin-induced renal cell apoptosis. Oncogene 25:4056–4066

    Article  CAS  Google Scholar 

  30. Ren D, Tu HC, Kim H, Wang GX, Bean GR, Takeuchi O, Jeffers JR, Zambetti GP, Hsieh JJ, Cheng EH (2010) BID, BIM, and PUMA are essential for activation of the BAX- and BAK-dependent cell death program. Science 330:1390–1393

    Article  CAS  Google Scholar 

  31. Zhang J, Huang K, O’Neill KL, Pang X, Luo X (2016) Bax/Bak activation in the absence of Bid, Bim, Puma, and p53. Cell Death Dis 7:e2266

    Article  CAS  Google Scholar 

  32. Zeng XH, Zeng XJ, Li YY (2003) Efficacy and safety of berberine for congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 92:173–176

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the Science and Technology Foundation of Tianjin Health Bureau (16KG101, 13KG105), the Natural Science Foundation of China (81700569, 81700659), the Natural Science Foundation of Tianjin (17JCYBJC28000) and the Integrated Western and Chinese Science Foundation of Tianjin Health Bureau (2017056).

Author information

Author notes

  1. Yuanbang Lin and Mingwei Sheng are contributed equally to this article.

Authors and Affiliations

  1. Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, 300052, China

    Yuanbang Lin & Ning Lu

  2. Department of Anesthesiology, Tianjin First Center Hospital, Tianjin, 300192, China

    Mingwei Sheng, Hongyin Du, Ning Lu & Wenli Yu

  3. First Central Clinical College, Tianjin Medical University, Tianjin, 300070, China

    Yijie Ding & Nan Zhang

  4. Department of Basic Medicine, Tianjin Medical University, Tianjin, 300010, China

    Yayue Song

Authors
  1. Yuanbang Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mingwei Sheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yijie Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yayue Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hongyin Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ning Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Wenli Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Author contributions

LYB: principal investigator, writing of the protocol, institutional review board submission, data collection, and writing the manuscript; SMW: data collection and analysis, study design and method, final review of data analysis, principal bio-statistician of the project; DYJ and ZN: writing the protocol, data review; SYY and DHY: study design review, monitor scientific process, maintaining patient confidentiality; YWL and LN: corresponding author, scientific advisor, study design, protocol review.

Corresponding authors

Correspondence to Ning Lu or Wenli Yu.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lin, Y., Sheng, M., Ding, Y. et al. Berberine protects renal tubular cells against hypoxia/reoxygenation injury via the Sirt1/p53 pathway. J Nat Med 72, 715–723 (2018). https://doi.org/10.1007/s11418-018-1210-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11418-018-1210-1

Keywords

Search

Navigation