Endotoxin-induced renal tolerance against ischemia and reperfusion injury is removed by iNOS, but not eNOS, gene-deletion

  • Kim, Jee-In (Department of Anatomy and BK21, Kyungpook National University School of Medicine) ;
  • Jang, Hee-Seong (Department of Anatomy and BK21, Kyungpook National University School of Medicine) ;
  • Park, Kwon-Moo (Department of Anatomy and BK21, Kyungpook National University School of Medicine)
  • Received : 2010.03.30
  • Accepted : 2010.06.30
  • Published : 2010.09.30


Endotoxin including lipopolysaccharide (LPS) confers organ tolerance against subsequent challenge by ischemia and reperfusion (I/R) insult. The mechanisms underlying this powerful adaptive defense remain to be defined. Therefore, in this study we attempted to determine whether nitric oxide (NO) and its associated enzymes, inducible NOS (iNOS) and endothelial NOS (eNOS, a constitutive NOS), are associated with LPS-induced renal tolerance against I/R injury, using iNOS (iNOS knock-out) or eNOS (eNOS knock-out) gene-deleted mice. A systemic low dose of LPS pretreatment protected kidney against I/R injury. LPS treatment increased the activity and expression of iNOS, but not eNOS, in kidney tissue. LPS pretreatment in iNOS, but not eNOS, knock-out mice did not protect kidney against I/R injury. In conclusion, the kidney tolerance to I/R injury conferred by pretreatment with LPS is mediated by increased expression and activation of iNOS.


Supported by : National Research Foundation of Korea (NRF)


  1. Wen, X., Murugan, R., Peng, Z. and Kellum, J. A. (2010) Pathophysiology of acute kidney injury: a new perspective. Contrib. Nephrol. 165, 39-45.
  2. Park, K. M., Kim, J. I., Ahn, Y., Bonventre, A. J. and Bonventre, J. V. (2004) Testosterone is responsible for enhanced susceptibility of males to ischemic renal injury. J. Biol. Chem. 279, 52282-52292.
  3. Kim, J., Jung, K. J. and Park, K. M. (2010) Reactive oxygen species differently regulate renal tubular epithelial and interstitial cell proliferation after ischemia and reperfusion injury. Am. J. Physiol. Renal. Physiol. 298, F1118-1129.
  4. Meng, X., Ao, L., Brown, J. M., Fullerton, D. A., Banerjee, A. and Harken, A. H. (1997) Nitric oxide synthase is not involved in cardiac contractile dysfunction in a rat model of endotoxemia without shock. Shock 7, 111-118.
  5. Heemann, U., Szabo, A., Hamar, P., Muller, V., Witzke, O., Lutz, J. and Philipp, T. (2000) Lipopolysaccharide pretreatment protects from renal ischemia/reperfusion injury: possible connection to an interleukin-6-dependent pathway. Am. J. Pathol. 156, 287-293.
  6. Wang, Y. P., Sato, C., Mizoguchi, K., Yamashita, Y., Oe, M. and Maeta, H. (2002) Lipopolysaccharide triggers late preconditioning against myocardial infarction via inducible nitric oxide synthase. Cardiovasc. Res. 56, 33-42.
  7. Zhao, L., Weber, P. A., Smith, J. R., Comerford, M. L. and Elliott, G. T. (1997) Role of inducible nitric oxide synthase in pharmacological “preconditioning” with monophosphoryl lipid A. J. Mol. Cell Cardiol. 29, 1567-1576.
  8. Elliott, G. T., Comerford, M. L., Smith, J. R. and Zhao, L. (1996) Myocardial ischemia/reperfusion protection using monophosphoryl lipid A is abrogated by the ATP-sensitive potassium channel blocker, glibenclamide. Cardiovasc. Res. 32, 1071-1080.
  9. Oreopoulos, G. D., Bradwell, S., Lu, Z., Fan, J., Khadaroo, R., Marshall, J. C., Li, Y. H. and Rotstein, O. D. (2001) Synergistic induction of IL-10 by hypertonic saline solution and lipopolysaccharides in murine peritoneal macrophages. Surgery 130, 157-165.
  10. Furuya, K., Zhu, L., Kawahara, N., Abe, O. and Kirino, T. (2005) Differences in infarct evolution between lipopolysaccharide- induced tolerant and nontolerant conditions to focal cerebral ischemia. J. Neurosurg. 103, 715-723.
  11. Hiasa, G., Hamada, M., Ikeda, S. and Hiwada, K. (2001) Ischemic preconditioning and lipopolysaccharide attenuate nuclear factor-kappaB activation and gene expression of inflammatory cytokines in the ischemia-reperfused rat heart. Jpn. Circ. J. 65, 984-990.
  12. Park, K. M., Chen, A. and Bonventre, J. V. (2001) Prevention of kidney ischemia/reperfusion-induced functional injury and JNK, p38, and MAPK kinase activation by remote ischemic pretreatment. J. Biol. Chem. 276, 11870-11876.
  13. Shames, B. D., Meldrum, D. R., Selzman, C. H., Pulido, E. J., Cain, B. S., Banerjee, A., Harken, A. H. and Meng, X. (1998) Increased levels of myocardial IkappaB-alpha protein promote tolerance to endotoxin. Am. J. Physiol. 275, H1084-1091.
  14. Park, K. M., Byun, J. Y., Kramers, C., Kim, J. I., Huang, P. L. and Bonventre, J. V. (2003) Inducible nitric-oxide synthase is an important contributor to prolonged protective effects of ischemic preconditioning in the mouse kidney. J. Biol. Chem. 278, 27256-27266.
  15. Elliott, G. T. (1998) Monophosphoryl lipid A induces delayed preconditioning against cardiac ischemia-reperfusion injury. J. Mol. Cell Cardiol. 30, 3-17.
  16. Kim, J., Jang, H. S. and Park, K. M. (2010) Reactive oxygen species generated by renal ischemia and reperfusion trigger protection against subsequent renal ischemia and reperfusion injury in mice. Am. J. Physiol. Renal. Physiol. 298, F158-166.
  17. Bonventre, J. V. (2002) Kidney ischemic preconditioning. Curr. Opin. Nephrol. Hypertens. 11, 43-48.
  18. Goligorsky, M. S., Brodsky, S. V. and Noiri, E. (2002) Nitric oxide in acute renal failure: NOS versus NOS. Kidney Int. 61, 855-861.
  19. Otani, H. (2009) The role of nitric oxide in myocardial repair and remodeling. Antioxid. Redox. Signal. 11, 1913-1928.
  20. Hamid, S. A., Bower, H. S. and Baxter, G. F. (2007) Rhokinase activation plays a major role as a mediator of irreversible injury in reperfused myocardium. Am. J. Physiol. Heart Circ. Physiol. 292, H2598-2606.
  21. Cuong, D. V., Kim, N., Youm, J. B., Joo, H., Warda, M., Lee, J. W., Park, W. S., Kim, T., Kang, S., Kim, H. and Han, J. (2006) Nitric oxide-cGMP-protein kinase G signaling pathway induces anoxic preconditioning through activation of ATP-sensitive K+ channels in rat hearts. Am. J. Physiol. Heart Circ. Physiol. 290, H1808-1817.
  22. Gao, F., Gao, E., Yue, T. L., Ohlstein, E. H., Lopez, B. L., Christopher, T. A. and Ma, X. L. (2002) Nitric oxide mediates the antiapoptotic effect of insulin in myocardial ischemia-reperfusion: the roles of PI3-kinase, Akt, and endothelial nitric oxide synthase phosphorylation. Circulation 105, 1497-1502.
  23. Bolli, R., Dawn, B., Tang, X. L., Qiu, Y., Ping, P., Xuan, Y. T., Jones, W. K., Takano, H., Guo, Y. and Zhang, J. (1998) The nitric oxide hypothesis of late preconditioning. Basic Res. Cardiol. 93, 325-338.
  24. Sheridan, A. M. and Bonventre, J. V. (2000) Cell biology and molecular mechanisms of injury in ischemic acute renal failure. Curr. Opin. Nephrol. Hypertens. 9, 427-434
  25. Nossaman, B. D. and Kadowitz, P. J. (2008) Potential benefits of peroxynitrite. Open Pharmacol. J. 2, 31-53.
  26. Nossaman, B. D., Bivalacqua, T. J., Champion, H. C., Baber, S. R. and Kadowitz, P. J. (2007) Analysis of vasodilator responses to peroxynitrite in the hindlimb vascular bed of the cat. J. Cardiovasc. Pharmacol. 50, 358-366.
  27. Liu, S., Beckman, J. S. and Ku, D. D. (1994) Peroxynitrite, a product of superoxide and nitric oxide, produces coronary vasorelaxation in dogs. J. Pharmacol. Exp. Ther. 268, 1114-1121.
  28. Lefer, D. J., Scalia, R., Campbell, B., Nossuli, T., Hayward, R., Salamon, M., Grayson, J. and Lefer, A. M. (1997) Peroxynitrite inhibits leukocyte-endothelial cell interactions and protects against ischemia-reperfusion injury in rats. J. Clin. Invest. 99, 684-691.

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