Skip to main content

Advertisement

SpringerLink
Log in

BML-111 Attenuates Renal Ischemia/Reperfusion Injury Via Peroxisome Proliferator-Activated Receptor-α-Regulated Heme Oxygenase-1

  • ORIGINAL ARTICLE
  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

We examine whether BML-111, a lipoxin receptor agonist, inhibits renal ischemia/reperfusion (I/R) injury, and whether peroxisome proliferator-activated receptor-α (PPARα) or heme oxygenase-1 (HO-1) is involved in protective effects of BML-111 on kidney against I/R injury. Rats subjected to renal I/R injury were treated with or without BML-111. Renal histological and immunohistochemical studies were performed. Expressions of phosphorylated p38 mitogen-activated protein kinase (pp38 MAPK), phosphorylated PPARα (pPPARα), and HO-1 were assessed in NRK-52E cells exposed to BML-111. The binding activity of PPARα to peroxisome proliferator-responsive element (PPRE) on HO-1 promoter in the cells was determined. BML-111 treatment resulted in a marked reduction in the severity of histological features of renal I/R injury, and attenuated the rise in renal myeloperoxidase and malondialdehyde, blood urea nitrogen and creatinine, urinary N-acetyl-β-glucosaminidase, and leucine aminopeptidase levels caused by I/R injury. BML-111 stimulated the renal expressions of pPPARα and HO-1, and cellular messenger RNA (mRNA) and protein expressions of pPPARα and HO-1 which were both blocked by GW6471, a selective PPARα antagonist, and ZnPP-IX, a specific inhibitor of HO-1 pretreatment. The pp38 MAPK inhibitor SB203580 blocked the BML-111-induced expressions of pp38 MAPK, pPPARα, and HO-1 in NRK-52E cells. The binding activity of PPARα to PPRE in nuclear extracts of NRK-52E cells was enhanced by treatment of the cells with BML-111, and was suppressed by GW6471 and SB203580. BML-111 protects the kidney against I/R injury via activation of p38 MAPK/PPARα/HO-1 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
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  1. Wen, X., R. Murugan, Z. Peng, and J.A. Kellum. 2010. Pathophysiology of acute kidney injury: a new perspective. Contributions to Nephrology 165: 39–45.

    Article  PubMed  Google Scholar 

  2. Eltzschig, H.K., and T. Eckle. 2011. Ischemia and reperfusion-from mechanism to translation. Nature Medicine 17: 1391–1401.

    Article  CAS  PubMed  Google Scholar 

  3. Chok, M.K., S. Ferlicot, M. Conti, A. Almolki, A. Dürrbach, S. Loric, et al. 2009. Renoprotective potency of heme oxygenase-1 induction in rat renal ischemia-reperfusion. Inflammation & Allergy Drug Targets 8: 252–259.

    Article  CAS  Google Scholar 

  4. Nath, K.A. 2006. Heme oxygenase-1: a provenance for cytoprotective pathways in the kidney and other tissues. Kidney International 70: 432–443.

    Article  CAS  PubMed  Google Scholar 

  5. Li Volti, G., V. Sorrenti, P. Murabito, F. Galvano, M. Veroux, A. Gullo, et al. 2007. Pharmacological induction of heme oxygenase-1 inhibits iNOS and oxidative stress in renal ischemia-reperfusion injury. Transplantation Proceedings 39: 2986–2991.

    Article  CAS  PubMed  Google Scholar 

  6. Patel, N.S.A., R. di Paola, E. Mazzon, D. Britti, C. Thiemermann, and S. Cuzzocrea. 2008. Peroxisome proliferator-activated receptor-α contributes to the resolution of inflammation after renal ischemia/reperfusion injury. Journal of Pharmacology and Experimental Therapeutics 328: 635–643.

    Article  PubMed  Google Scholar 

  7. Miglio, G., A.C. Rosa, L. Rattazzi, C. Grange, M. Collino, G. Camussi, et al. 2011. The subtypes of peroxisome proliferator-activated receptors expressed by human podocytes and their role in decreasing podocyte injury. British Journal of Pharmacology 162: 111–125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Cheng, C.F., W.S. Lian, S.H. Chen, P.F. Lai, H.F. Li, Y.F. Lan, et al. 2012. Protective effects of adiponectin against renal ischemia-reperfusion injury via prostacyclin-PPARα-heme oxygenase-1 signaling pathway. Journal of Cellular Physiology 227: 239–249.

    Article  CAS  PubMed  Google Scholar 

  9. Li, S., K.K. Nagothu, V. Desai, T. Lee, W. Branham, C. Molan, et al. 2009. Transgenic expression of peroxisome proliferator-activated receptor-α in mice confers protection during acute kidney injury. Kidney International 76: 1049–1062.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Chen, H.H., T.W. Chen, and H. Lin. 2009. Prostacycin-induced peroxisome proliferator-activated receptor-α translocation attenuates NF-κB and TNF-α activation after renal ischemia-reperfusion injury. American Journal of Physiology. Renal Physiology 297: F1109–F1118.

    Article  CAS  PubMed  Google Scholar 

  11. Chen, H.H., T.W. Chen, and H. Lin. 2010. Pravastatin attenuates carboplatin-induced nephrotoxicity in rodents via peroxisome proliferator-activated receptor α-regulated heme oxygenase-1. Molecular Pharmacology 78: 36–45.

    Article  CAS  PubMed  Google Scholar 

  12. Serhan, C.N. 2014. Novel pro-resolving lipid mediators in inflammation are leads for resolution physiologyas. Nature 510: 92–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Serhan, C.N., and N. Chiang. 2008. Endogenous pro-resolving and anti-inflammatory lipid mediators: a new pharmacologic genus. British Journal of Pharmacology 153: S200–S215.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Nascimento-Silva, V., M.A. Arruda, C. Barja-Fidalgo, and I.M. Fierro. 2007. Aspirin-triggered lipoxin A4 blocks reactive oxygen species generation in endothelial cells: a novel antioxidative mechanism. Thrombosis and Haemostasis 97: 88–98.

    CAS  PubMed  Google Scholar 

  15. Leonard, M.O., K. Nannan, M.J. Burne, D.W.P. Lappin, P. Doran, P. Coleman, et al. 2002. 15-epi-15-(para-fluorophenoxy)- lipoxin A4-methyl ester, a synthetic analogue of 15-epi-lipoxin A4, is protective in experimental ischemic acute renal failure. Journal of the American Society of Nephrology 13: 1657–1662.

    Article  CAS  PubMed  Google Scholar 

  16. Kieran, N.E., P.P. Doran, S.B. Connolly, M.C. Greenan, D.F. Higgins, M. Leonard, et al. 2003. Modification of the transcriptomic response to renal ischemia/reperfusion injury by lipoxin analog. Kidney International 64: 480–492.

    Article  CAS  PubMed  Google Scholar 

  17. Nascimento-Silva, V., M.A. Arruda, C. Barja-Fidalgo, C.G. Villela, and I.M. Fierro. 2005. Novel lipid mediator aspirin-triggered lipoxin A4 induces heme oxygenase-1 in endothelial cells. American Journal of Physiology. Cell Physiology 289: C557–C563.

    Article  CAS  PubMed  Google Scholar 

  18. Biteman, B., I.R. Hassan, E. Walker, A.J. Leedom, M. Dunn, F. Seta, et al. 2007. Interdependence of lipoxin A4 and heme-oxygenase in counter-regulating inflammation during corneal wound healing. FASEB Journal 21: 2257–2266.

    Article  CAS  PubMed  Google Scholar 

  19. Jin, S.W., L. Zhang, Q.Q. Lian, D. Liu, P. Wu, S.L. Yao, et al. 2007. Posttreatment with aspirin-triggered lipoxin A4 analog attenuates lipopolysaccharide-induced acute lung injury in mice: the role of heme oxygenase-1. Anesthesia and Analgesia 104: 369–377.

    Article  CAS  PubMed  Google Scholar 

  20. Chen, X.Q., S.H. Wu, Y. Zhou, and Y.R. Tang. 2013. Lipoxin A4-induced heme oxygenase-1 protects cardiomyocytes against hypoxia/reoxygenation injury via p38 MAPK activation and Nrf2/ARE complex. PLoS One 8, e67120.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Chen, X.Q., S.H. Wu, Y. Zhou, and Y.R. Tang. 2013. Involvement of K+ channel-dependent pathways in lipoxin A4-induced protective effects on hypoxia/reoxygenation injury of cardiomyocytes. Prostaglandins, Leukotrienes, and Essential Fatty Acids 88: 391–397.

    Article  CAS  PubMed  Google Scholar 

  22. Sobrado, M., M.P. Pereira, I. Ballesteros, O. Hurtado, D. Fernandez-Lopez, J.M. Pradillo, et al. 2009. Synthesis of lipoxin A4 by 5-lipoxygenase mediates PPARγ-dependent, neuroprotective effects of rosiglitazone in experimental stroke. Journal of Neuroscience 29: 3875–3884.

    Article  CAS  PubMed  Google Scholar 

  23. Weinberger, B., C. Quizon, A.M. Vetrano, F. Archer, J.D. Laskin, and D.L. Laskin. 2008. Mechanisms mediating reduced responsiveness of neonatal neutrophils to lipoxin A4. Pediatric Research 64: 393–398.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. McMahon, B., C. Stenson, F. McPhillips, A. Fanning, H.R. Brady, and C. Godson. 2000. Lipoxin A4 antagonizes the mitogenic effects of leukotriene D4 in human renal mesangial cells. Journal of Biological Chemistry 275: 27566–27575.

    CAS  PubMed  Google Scholar 

  25. Lin, H., C.H. Yu, C.Y. Jen, C.F. Cheng, Y. Chou, C.C. Chang, et al. 2010. Adiponection-mediated heme oxygenase-1 induction protects against iron-induced liver injury via a PPARα-dependent mechanism. American Journal of Pathology 177: 1697–1709.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wu, S.H., Y.M. Zhang, H.X. Tao, and L. Dong. 2010. Lipoxin A4 inhibits transition of epithelial to mesenchymal cells in proximal tubules. American Journal of Nephrology 32: 122–136.

    Article  CAS  PubMed  Google Scholar 

  27. Wu, S.H., X.H. Wu, C. Lu, L. Dong, G.P. Zhou, and Z.Q. Chen. 2006. Lipoxin A4 inhibits connective tissue growth factor-induced production of chemokines in rat mesangial cells. Kidney International 69: 248–256.

    Article  CAS  PubMed  Google Scholar 

  28. Wu, S.H., P.Y. Liao, L. Dong, and Z.Q. Chen. 2008. Signal pathway involved in inhibition by lipoxin A4 of production of interleukins in endothelial cells by lipopolysaccharide. Inflammation Research 57: 430–437.

    Article  CAS  PubMed  Google Scholar 

  29. Wu, S.H., X.H. Wu, P.Y. Liao, and L. Dong. 2007. Signal transduction involved in protective effects of 15(R/S)-methyl- lipoxin A4 on mesangioproliferative nephritis in rats. Prostaglandins, Leukotrienes, and Essential Fatty Acids 76: 173–180.

    Article  CAS  PubMed  Google Scholar 

  30. Zhang, L., X. Zhang, P. Wu, H. Li, S. Jin, X. Zhou, et al. 2008. BML-111, a lipoxin receptor agonist, modulates the immune response and reduces the severity of collagen-induced arthritis. Inflammation Research 57: 157–162.

    Article  CAS  PubMed  Google Scholar 

  31. Kieran, N.E., P. Maderna, and C. Godson. 2004. Lipoxins: potential anti-inflammatory, proresolution, and antifibrotic mediators in renal disease. Kidney International 65: 1145–1154.

    Article  CAS  PubMed  Google Scholar 

  32. Ohse, T., T. Ota, N. Kieran, C. Godson, K. Yamada, T. Tanaka, et al. 2004. Modulation of interferon-induced genes by lipoxin analogue in anti-glomerular membrane nephritis. Journal of the American Society of Nephrology 15: 919–927.

    Article  CAS  PubMed  Google Scholar 

  33. Deng, L.L., L. Zhong, J.R. Lei, L. Tang, L. Liu, S.Q. Xie, et al. 2012. Protective effect of lipoxin A4 against rhabdomyolysis-induced acute kidney injury in rats. Chin J Cell Mol Immunol 28: 907–910 (in Chinese with English abstract).

    CAS  Google Scholar 

  34. Brennan, E.P., K.A. Nolan, E. Börgeson, O.S. Gough, C.M. McEvoy, N.G. Docherty, et al. 2013. Lipoxins attenuate renal fibrosis by inducing let-7c and suppressing TGFβR1. Journal of the American Society of Nephrology 24: 627–637.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Börgeson, E., N.G. Docherty, M. Murphy, K. Rodgers, A. Ryan, T.P. O'Sullivan, et al. 2011. Lipoxin A4 and benzo-lipoxin A4 attenuate experimental renal fibrosis. FASEB Journal 25: 2967–2979.

    Article  PubMed  Google Scholar 

  36. Börgeson, E., A.M.F. Johnson, Y.S. Lee, A. Till, G.H. Syed, S.T. Ali-Shah, et al. 2015. Lipoxin A4 attenuates obesity-induced adipose inflammation and associated liver and kidney disease. Cell Metabolism 22: 1–13.

    Article  Google Scholar 

  37. Zhang, L., J. Wan, H. Li, P. Wu, S. Jin, X. Zhou, et al. 2007. Protective effects of BML-111, a lipoxin A4 receptor agonist, on carbon tetrachloride-induced liver injury in mice. Hepatology Research 37: 948–956.

    Article  CAS  PubMed  Google Scholar 

  38. Gong, J., S. Guo, H.B. Li, S.Y. Yuan, Y. Shang, and S.L. Yao. 2012. BML-111, a lipoxin receptor agonist, protects haemorrhagic shock-induced acute lung injury in rats. Resuscitation 83: 907–912.

    Article  CAS  PubMed  Google Scholar 

  39. Hawkins, K.E., K.M. DeMars, J. Singh, C. Yang, H.S. Cho, J.C. Frankowski, et al. 2014. Neurovascular protection by post-ischemic intravenous injections of the lipoxin A4 receptor agonist, BML-111, in a rat model of ischemic stroke. Journal of Neurochemistry 129: 130–142.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wang, Y.Z., Y.C. Zhang, J.S. Cheng, Q. Ni, P.W. Li, W. Han, et al. 2014. Protective effects of BML-111 on cerulein-induced acute pancreatitis-associated lung injury via activation of Nrf2/ARE signaling pathway. Inflammation 37(4): 1120–1133.

    Article  CAS  PubMed  Google Scholar 

  41. Park, S.Y., J.U. Bae, K.W. Hong, and C.D. Kim. 2011. HO-1 induced by cilostazol protects against TNF-α-associated cytotoxicity via a PPAR-γ-dependent pathway in human endothelial cells. Korean J Physiol Pharmacol 15: 83–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Krönke, G., A. Kadl, E. Ikonomu, S. Blüml, A. Fürnkranz, I.J. Sarembock, et al. 2007. Expression of heme oxygenase-1 in human vascular cells is regulated by peroxisome proliferator-activated receptors. Arteriosclerosis, Thrombosis, and Vascular Biology 27: 1276–1282.

    Article  PubMed  Google Scholar 

Download references

Acknowledgement

This work was supported by the National Natural Scientific Grand (No. 81270821 and No. 81300521) from the Government of China, and by the Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions (JX10231801).

Author information

Authors and Affiliations

  1. Department of Pediatrics, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, People’s Republic of China

    Sheng-Hua Wu, Xiao-Qing Chen, Jing Lü & Ming-Jie Wang

Authors
  1. Sheng-Hua Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiao-Qing Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jing Lü
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ming-Jie Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sheng-Hua Wu.

Ethics declarations

Conflict of Interest

None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, SH., Chen, XQ., Lü, J. et al. BML-111 Attenuates Renal Ischemia/Reperfusion Injury Via Peroxisome Proliferator-Activated Receptor-α-Regulated Heme Oxygenase-1. Inflammation 39, 611–624 (2016). https://doi.org/10.1007/s10753-015-0286-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-015-0286-y

KEY WORDS

Search

Navigation