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. 1996 Feb 15;97(4):1056–1063. doi: 10.1172/JCI118498

Intercellular adhesion molecule-1-deficient mice are protected against ischemic renal injury.

K J Kelly 1, W W Williams Jr 1, R B Colvin 1, S M Meehan 1, T A Springer 1, J C Gutierrez-Ramos 1, J V Bonventre 1
PMCID: PMC507153  PMID: 8613529

Abstract

Studies in the rat have pointed to a role for intercellular adhesion molecule-1 (ICAM-1) in the pathogenesis of acute tubular necrosis. These studies used antibodies, which may have nonspecific effects. We report that renal ICAM-1 mRNA levels and systemic levels of the cytokines IL-1 and TNF-alpha increase 1 h after ischemia/ reperfusion in the mouse. We sought direct proof for a critical role for ICAM-1 in the pathophysiology of ischemic renal failure using mutant mice genetically deficient in ICAM-1. ICAM-1 is undetectable in mutant mice in contrast with normal mice, in which ICAM-1 is prominent in the endothelium of the vasa recta. Mutant mice are protected from acute renal ischemic injury as judged by serum creatinine, renal histology, and animal survival . Renal leukocyte infiltration, quantitated morphologically and by measuring tissue myeloperoxidase, was markedly less in ICAM-1-deficient than control mice. To evaluate whether prevention of neutrophil infiltration could be responsible for the protection observed in the mutant mice, we treated normal mice with antineutrophil serum to reduce absolute neutrophil counts to < 100 cells/mm3. These neutrophil-depleted animals were protected against ischemic renal failure. Anti-1CAm-1 antibody protected normal mice against renal ischemic injury but did not provide additional protection to neutrophil-depleted animals. Thus, ICAM-1 is a key mediator of ischemic acute renal failure likely acting via potentiation of neutrophilendothelial interactions.

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Selected References

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  1. Ballantyne C. M., O'Brien W. E., Beaudet A. L. Nucleotide sequence of the cDNA for murine intercellular adhesion molecule-1 (ICAM-1). Nucleic Acids Res. 1989 Jul 25;17(14):5853–5853. doi: 10.1093/nar/17.14.5853. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bonventre J. V. Mechanisms of ischemic acute renal failure. Kidney Int. 1993 May;43(5):1160–1178. doi: 10.1038/ki.1993.163. [DOI] [PubMed] [Google Scholar]
  3. Bradley P. P., Priebat D. A., Christensen R. D., Rothstein G. Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker. J Invest Dermatol. 1982 Mar;78(3):206–209. doi: 10.1111/1523-1747.ep12506462. [DOI] [PubMed] [Google Scholar]
  4. Colletti L. M., Remick D. G., Burtch G. D., Kunkel S. L., Strieter R. M., Campbell D. A., Jr Role of tumor necrosis factor-alpha in the pathophysiologic alterations after hepatic ischemia/reperfusion injury in the rat. J Clin Invest. 1990 Jun;85(6):1936–1943. doi: 10.1172/JCI114656. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Fine J. S., Kruisbeek A. M. The role of LFA-1/ICAM-1 interactions during murine T lymphocyte development. J Immunol. 1991 Nov 1;147(9):2852–2859. [PubMed] [Google Scholar]
  6. Forman M. B., Virmani R., Puett D. W. Mechanisms and therapy of myocardial reperfusion injury. Circulation. 1990 Mar;81(3 Suppl):IV69–IV78. [PubMed] [Google Scholar]
  7. Granger D. N., Korthuis R. J. Physiologic mechanisms of postischemic tissue injury. Annu Rev Physiol. 1995;57:311–332. doi: 10.1146/annurev.ph.57.030195.001523. [DOI] [PubMed] [Google Scholar]
  8. Guidot D. M., Linas S. L., Repine M. J., Shanley P. F., Fisher H. S., Repine J. E. Interleukin-1 treatment increases neutrophils but not antioxidant enzyme activity or resistance to ischemia-reperfusion injury in rat kidneys. Inflammation. 1994 Oct;18(5):537–545. doi: 10.1007/BF01560700. [DOI] [PubMed] [Google Scholar]
  9. Hallenbeck J. M., Dutka A. J., Tanishima T., Kochanek P. M., Kumaroo K. K., Thompson C. B., Obrenovitch T. P., Contreras T. J. Polymorphonuclear leukocyte accumulation in brain regions with low blood flow during the early postischemic period. Stroke. 1986 Mar-Apr;17(2):246–253. doi: 10.1161/01.str.17.2.246. [DOI] [PubMed] [Google Scholar]
  10. Haug C. E., Colvin R. B., Delmonico F. L., Auchincloss H., Jr, Tolkoff-Rubin N., Preffer F. I., Rothlein R., Norris S., Scharschmidt L., Cosimi A. B. A phase I trial of immunosuppression with anti-ICAM-1 (CD54) mAb in renal allograft recipients. Transplantation. 1993 Apr;55(4):766–773. doi: 10.1097/00007890-199304000-00016. [DOI] [PubMed] [Google Scholar]
  11. Hellberg P. O., Källskog O. T., Ojteg G., Wolgast M. Peritubular capillary permeability and intravascular RBC aggregation after ischemia: effects of neutrophils. Am J Physiol. 1990 Apr;258(4 Pt 2):F1018–F1025. doi: 10.1152/ajprenal.1990.258.4.F1018. [DOI] [PubMed] [Google Scholar]
  12. Horley K. J., Carpenito C., Baker B., Takei F. Molecular cloning of murine intercellular adhesion molecule (ICAM-1). EMBO J. 1989 Oct;8(10):2889–2896. doi: 10.1002/j.1460-2075.1989.tb08437.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Inauen W., Granger D. N., Meininger C. J., Schelling M. E., Granger H. J., Kvietys P. R. An in vitro model of ischemia/reperfusion-induced microvascular injury. Am J Physiol. 1990 Jul;259(1 Pt 1):G134–G139. doi: 10.1152/ajpgi.1990.259.1.G134. [DOI] [PubMed] [Google Scholar]
  14. Kelly K. J., Williams W. W., Jr, Colvin R. B., Bonventre J. V. Antibody to intercellular adhesion molecule 1 protects the kidney against ischemic injury. Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):812–816. doi: 10.1073/pnas.91.2.812. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Klausner J. M., Paterson I. S., Goldman G., Kobzik L., Rodzen C., Lawrence R., Valeri C. R., Shepro D., Hechtman H. B. Postischemic renal injury is mediated by neutrophils and leukotrienes. Am J Physiol. 1989 May;256(5 Pt 2):F794–F802. doi: 10.1152/ajprenal.1989.256.5.F794. [DOI] [PubMed] [Google Scholar]
  16. Kornberg L. J., Earp H. S., Turner C. E., Prockop C., Juliano R. L. Signal transduction by integrins: increased protein tyrosine phosphorylation caused by clustering of beta 1 integrins. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8392–8396. doi: 10.1073/pnas.88.19.8392. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Languino L. R., Plescia J., Duperray A., Brian A. A., Plow E. F., Geltosky J. E., Altieri D. C. Fibrinogen mediates leukocyte adhesion to vascular endothelium through an ICAM-1-dependent pathway. Cell. 1993 Jul 2;73(7):1423–1434. doi: 10.1016/0092-8674(93)90367-y. [DOI] [PubMed] [Google Scholar]
  18. Lefer A. M., Tsao P. S., Lefer D. J., Ma X. L. Role of endothelial dysfunction in the pathogenesis of reperfusion injury after myocardial ischemia. FASEB J. 1991 Apr;5(7):2029–2034. doi: 10.1096/fasebj.5.7.2010056. [DOI] [PubMed] [Google Scholar]
  19. Linas S. L., Shanley P. F., Whittenburg D., Berger E., Repine J. E. Neutrophils accentuate ischemia-reperfusion injury in isolated perfused rat kidneys. Am J Physiol. 1988 Oct;255(4 Pt 2):F728–F735. doi: 10.1152/ajprenal.1988.255.4.F728. [DOI] [PubMed] [Google Scholar]
  20. Linas S. L., Whittenburg D., Parsons P. E., Repine J. E. Mild renal ischemia activates primed neutrophils to cause acute renal failure. Kidney Int. 1992 Sep;42(3):610–616. doi: 10.1038/ki.1992.325. [DOI] [PubMed] [Google Scholar]
  21. Malis C. D., Leaf A., Varadarajan G. S., Newell J. B., Weber P. C., Force T., Bonventre J. V. Effects of dietary omega 3 fatty acids on vascular contractility in preanoxic and postanoxic aortic rings. Circulation. 1991 Sep;84(3):1393–1401. doi: 10.1161/01.cir.84.3.1393. [DOI] [PubMed] [Google Scholar]
  22. Mason J., Joeris B., Welsch J., Kriz W. Vascular congestion in ischemic renal failure: the role of cell swelling. Miner Electrolyte Metab. 1989;15(3):114–124. [PubMed] [Google Scholar]
  23. Minami M., Kuraishi Y., Yabuuchi K., Yamazaki A., Satoh M. Induction of interleukin-1 beta mRNA in rat brain after transient forebrain ischemia. J Neurochem. 1992 Jan;58(1):390–392. doi: 10.1111/j.1471-4159.1992.tb09324.x. [DOI] [PubMed] [Google Scholar]
  24. Olof P., Hellberg A., Källskog O., Wolgast M. Red cell trapping and postischemic renal blood flow. Differences between the cortex, outer and inner medulla. Kidney Int. 1991 Oct;40(4):625–631. doi: 10.1038/ki.1991.254. [DOI] [PubMed] [Google Scholar]
  25. Ouellette A. J., Malt R. A., Sukhatme V. P., Bonventre J. V. Expression of two "immediate early" genes, Egr-1 and c-fos, in response to renal ischemia and during compensatory renal hypertrophy in mice. J Clin Invest. 1990 Mar;85(3):766–771. doi: 10.1172/JCI114502. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Paller M. S. Effect of neutrophil depletion on ischemic renal injury in the rat. J Lab Clin Med. 1989 Mar;113(3):379–386. [PubMed] [Google Scholar]
  27. Rabb H., Mendiola C. C., Dietz J., Saba S. R., Issekutz T. B., Abanilla F., Bonventre J. V., Ramirez G. Role of CD11a and CD11b in ischemic acute renal failure in rats. Am J Physiol. 1994 Dec;267(6 Pt 2):F1052–F1058. doi: 10.1152/ajprenal.1994.267.6.F1052. [DOI] [PubMed] [Google Scholar]
  28. Rabb H., Mendiola C. C., Saba S. R., Dietz J. R., Smith C. W., Bonventre J. V., Ramirez G. Antibodies to ICAM-1 protect kidneys in severe ischemic reperfusion injury. Biochem Biophys Res Commun. 1995 Jun 6;211(1):67–73. doi: 10.1006/bbrc.1995.1779. [DOI] [PubMed] [Google Scholar]
  29. Sakr M., Zetti G., McClain C., Gavaler J., Nalesnik M., Todo S., Starzl T., Van Thiel D. The protective effect of FK506 pretreatment against renal ischemia/reperfusion injury in rats. Transplantation. 1992 May;53(5):987–991. doi: 10.1097/00007890-199205000-00004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Schachner M. The analysis of neural recognition molecules: benefits and vicissitudes of functional knock-outs using antibodies and gene ablation. Curr Opin Cell Biol. 1993 Oct;5(5):786–790. doi: 10.1016/0955-0674(93)90026-m. [DOI] [PubMed] [Google Scholar]
  31. Schuch U., Lohse M. J., Schachner M. Neural cell adhesion molecules influence second messenger systems. Neuron. 1989 Jul;3(1):13–20. doi: 10.1016/0896-6273(89)90111-6. [DOI] [PubMed] [Google Scholar]
  32. Sligh J. E., Jr, Ballantyne C. M., Rich S. S., Hawkins H. K., Smith C. W., Bradley A., Beaudet A. L. Inflammatory and immune responses are impaired in mice deficient in intercellular adhesion molecule 1. Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8529–8533. doi: 10.1073/pnas.90.18.8529. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Springer T. A. Adhesion receptors of the immune system. Nature. 1990 Aug 2;346(6283):425–434. doi: 10.1038/346425a0. [DOI] [PubMed] [Google Scholar]
  34. Takei F. Inhibition of mixed lymphocyte response by a rat monoclonal antibody to a novel murine lymphocyte activation antigen (MALA-2). J Immunol. 1985 Mar;134(3):1403–1407. [PubMed] [Google Scholar]
  35. Thornton M. A., Winn R., Alpers C. E., Zager R. A. An evaluation of the neutrophil as a mediator of in vivo renal ischemic-reperfusion injury. Am J Pathol. 1989 Sep;135(3):509–515. [PMC free article] [PubMed] [Google Scholar]
  36. Werb Z., Tremble P. M., Behrendtsen O., Crowley E., Damsky C. H. Signal transduction through the fibronectin receptor induces collagenase and stromelysin gene expression. J Cell Biol. 1989 Aug;109(2):877–889. doi: 10.1083/jcb.109.2.877. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Xu H., Gonzalo J. A., St Pierre Y., Williams I. R., Kupper T. S., Cotran R. S., Springer T. A., Gutierrez-Ramos J. C. Leukocytosis and resistance to septic shock in intercellular adhesion molecule 1-deficient mice. J Exp Med. 1994 Jul 1;180(1):95–109. doi: 10.1084/jem.180.1.95. [DOI] [PMC free article] [PubMed] [Google Scholar]

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