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. 1997 Jun 1;99(11):2682–2690. doi: 10.1172/JCI119457

The cytokine-adhesion molecule cascade in ischemia/reperfusion injury of the rat kidney. Inhibition by a soluble P-selectin ligand.

M Takada 1, K C Nadeau 1, G D Shaw 1, K A Marquette 1, N L Tilney 1
PMCID: PMC508114  PMID: 9169498

Abstract

Ischemia/reperfusion (I/R) injury associated with renal transplantation may influence both early graft function and late changes. The initial (</= 7 d) events of warm and in situ perfused cold ischemia of native kidneys in uninephrectomized rats were examined. mRNA expression of the early adhesion molecule, E-selectin, peaked within 6 h; PMNs infiltrated in parallel. T cells and macrophages entered the injured kidney by 2-5 d; the associated upregulation of MHC class II antigen expression suggested increased immunogenicity of the organ. Th1 products (IL-2, TNFalpha, IFNgamma) and macrophage-associated products (IL-1, IL-6, TGFbeta) remained highly expressed after 2 d. To examine directly the effects of selectins in I/R injury, a soluble P-selectin glycoprotein ligand (sPSGL) was used. Ischemic kidneys were perfused in situ with 5 microg of sPSGL in UW solution; 50 microg was administered intravenously 3 h after reperfusion. E-selectin mRNA remained at baseline, leukocytes did not infiltrate the injured organs throughout the 7-d period, and their associated products were markedly inhibited. Class II expression did not increase. No renal dysfunction secondary to I/R occurred. The early changes of I/R injury may be prevented by treatment with soluble P- and E-selectin ligand. This may reduce subsequent host inflammatory responses after transplantation.

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Selected References

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  1. Almond P. S., Matas A., Gillingham K., Dunn D. L., Payne W. D., Gores P., Gruessner R., Najarian J. S. Risk factors for chronic rejection in renal allograft recipients. Transplantation. 1993 Apr;55(4):752–757. doi: 10.1097/00007890-199304000-00013. [DOI] [PubMed] [Google Scholar]
  2. Andrews P. A., Finn J. E., Lloyd C. M., Zhou W., Mathieson P. W., Sacks S. H. Expression and tissue localization of donor-specific complement C3 synthesized in human renal allografts. Eur J Immunol. 1995 Apr;25(4):1087–1093. doi: 10.1002/eji.1830250434. [DOI] [PubMed] [Google Scholar]
  3. Asa D., Raycroft L., Ma L., Aeed P. A., Kaytes P. S., Elhammer A. P., Geng J. G. The P-selectin glycoprotein ligand functions as a common human leukocyte ligand for P- and E-selectins. J Biol Chem. 1995 May 12;270(19):11662–11670. doi: 10.1074/jbc.270.19.11662. [DOI] [PubMed] [Google Scholar]
  4. Baldwin W. M., 3rd, Pruitt S. K., Brauer R. B., Daha M. R., Sanfilippo F. Complement in organ transplantation. Contributions to inflammation, injury, and rejection. Transplantation. 1995 Mar 27;59(6):797–808. [PubMed] [Google Scholar]
  5. Berman C. L., Yeo E. L., Wencel-Drake J. D., Furie B. C., Ginsberg M. H., Furie B. A platelet alpha granule membrane protein that is associated with the plasma membrane after activation. Characterization and subcellular localization of platelet activation-dependent granule-external membrane protein. J Clin Invest. 1986 Jul;78(1):130–137. doi: 10.1172/JCI112542. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bevilacqua M. P., Stengelin S., Gimbrone M. A., Jr, Seed B. Endothelial leukocyte adhesion molecule 1: an inducible receptor for neutrophils related to complement regulatory proteins and lectins. Science. 1989 Mar 3;243(4895):1160–1165. doi: 10.1126/science.2466335. [DOI] [PubMed] [Google Scholar]
  7. Bierhuizen M. F., Fukuda M. Expression cloning of a cDNA encoding UDP-GlcNAc:Gal beta 1-3-GalNAc-R (GlcNAc to GalNAc) beta 1-6GlcNAc transferase by gene transfer into CHO cells expressing polyoma large tumor antigen. Proc Natl Acad Sci U S A. 1992 Oct 1;89(19):9326–9330. doi: 10.1073/pnas.89.19.9326. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Bischoff J., Brasel C. Regulation of P-selectin by tumor necrosis factor-alpha. Biochem Biophys Res Commun. 1995 May 5;210(1):174–180. doi: 10.1006/bbrc.1995.1643. [DOI] [PubMed] [Google Scholar]
  9. Bulkley G. B. Reactive oxygen metabolites and reperfusion injury: aberrant triggering of reticuloendothelial function. Lancet. 1994 Oct 1;344(8927):934–936. doi: 10.1016/s0140-6736(94)92276-4. [DOI] [PubMed] [Google Scholar]
  10. Böttger E. C., Blanar M. A., Flavell R. A. Cycloheximide, an inhibitor of protein synthesis, prevents gamma-interferon-induced expression of class II mRNA in a macrophage cell line. Immunogenetics. 1988;28(4):215–220. doi: 10.1007/BF00345497. [DOI] [PubMed] [Google Scholar]
  11. Carpenter C. B. Long-term failure of renal transplants: adding insult to injury. Kidney Int Suppl. 1995 Aug;50:S40–S44. [PubMed] [Google Scholar]
  12. Chehadeh H. E., Zerlauth G., Mannhalter J. W. Video image analysis of quantitative competitive PCR products: comparison of different evaluation methods. Biotechniques. 1995 Jan;18(1):26–28. [PubMed] [Google Scholar]
  13. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  14. De Luca M., Dunlop L. C., Andrews R. K., Flannery J. V., Jr, Ettling R., Cumming D. A., Veldman G. M., Berndt M. C. A novel cobra venom metalloproteinase, mocarhagin, cleaves a 10-amino acid peptide from the mature N terminus of P-selectin glycoprotein ligand receptor, PSGL-1, and abolishes P-selectin binding. J Biol Chem. 1995 Nov 10;270(45):26734–26737. doi: 10.1074/jbc.270.45.26734. [DOI] [PubMed] [Google Scholar]
  15. Frenette P. S., Mayadas T. N., Rayburn H., Hynes R. O., Wagner D. D. Susceptibility to infection and altered hematopoiesis in mice deficient in both P- and E-selectins. Cell. 1996 Feb 23;84(4):563–574. doi: 10.1016/s0092-8674(00)81032-6. [DOI] [PubMed] [Google Scholar]
  16. Garcia-Criado F. J., Toledo-Pereyra L. H., Lopez-Neblina F., Phillips M. L., Paez-Rollys A., Misawa K. Role of P-selectin in total hepatic ischemia and reperfusion. J Am Coll Surg. 1995 Oct;181(4):327–334. [PubMed] [Google Scholar]
  17. Goes N., Urmson J., Ramassar V., Halloran P. F. Ischemic acute tubular necrosis induces an extensive local cytokine response. Evidence for induction of interferon-gamma, transforming growth factor-beta 1, granulocyte-macrophage colony-stimulating factor, interleukin-2, and interleukin-10. Transplantation. 1995 Feb 27;59(4):565–572. [PubMed] [Google Scholar]
  18. Gotsch U., Jäger U., Dominis M., Vestweber D. Expression of P-selectin on endothelial cells is upregulated by LPS and TNF-alpha in vivo. Cell Adhes Commun. 1994 Apr;2(1):7–14. doi: 10.3109/15419069409014198. [DOI] [PubMed] [Google Scholar]
  19. Grober J. S., Bowen B. L., Ebling H., Athey B., Thompson C. B., Fox D. A., Stoolman L. M. Monocyte-endothelial adhesion in chronic rheumatoid arthritis. In situ detection of selectin and integrin-dependent interactions. J Clin Invest. 1993 Jun;91(6):2609–2619. doi: 10.1172/JCI116500. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Guyer D. A., Moore K. L., Lynam E. B., Schammel C. M., Rogelj S., McEver R. P., Sklar L. A. P-selectin glycoprotein ligand-1 (PSGL-1) is a ligand for L-selectin in neutrophil aggregation. Blood. 1996 Oct 1;88(7):2415–2421. [PubMed] [Google Scholar]
  21. Hamburger S. A., McEver R. P. GMP-140 mediates adhesion of stimulated platelets to neutrophils. Blood. 1990 Feb 1;75(3):550–554. [PubMed] [Google Scholar]
  22. Hancock W. W., Lord R. H., Colby A. J., Diamantstein T., Rickles F. R., Dijkstra C., Hogg N., Tilney N. L. Identification of IL 2R+ T cells and macrophages within rejecting rat cardiac allografts, and comparison of the effects of treatment with anti-IL 2R monoclonal antibody or cyclosporin. J Immunol. 1987 Jan 1;138(1):164–170. [PubMed] [Google Scholar]
  23. Johnson R. C., Mayadas T. N., Frenette P. S., Mebius R. E., Subramaniam M., Lacasce A., Hynes R. O., Wagner D. D. Blood cell dynamics in P-selectin-deficient mice. Blood. 1995 Aug 1;86(3):1106–1114. [PubMed] [Google Scholar]
  24. Kansas G. S. Selectins and their ligands: current concepts and controversies. Blood. 1996 Nov 1;88(9):3259–3287. [PubMed] [Google Scholar]
  25. Kaufman R. J., Davies M. V., Wasley L. C., Michnick D. Improved vectors for stable expression of foreign genes in mammalian cells by use of the untranslated leader sequence from EMC virus. Nucleic Acids Res. 1991 Aug 25;19(16):4485–4490. doi: 10.1093/nar/19.16.4485. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. 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]
  27. Khew-Goodall Y., Butcher C. M., Litwin M. S., Newlands S., Korpelainen E. I., Noack L. M., Berndt M. C., Lopez A. F., Gamble J. R., Vadas M. A. Chronic expression of P-selectin on endothelial cells stimulated by the T-cell cytokine, interleukin-3. Blood. 1996 Feb 15;87(4):1432–1438. [PubMed] [Google Scholar]
  28. Kukowska-Latallo J. F., Larsen R. D., Nair R. P., Lowe J. B. A cloned human cDNA determines expression of a mouse stage-specific embryonic antigen and the Lewis blood group alpha(1,3/1,4)fucosyltransferase. Genes Dev. 1990 Aug;4(8):1288–1303. doi: 10.1101/gad.4.8.1288. [DOI] [PubMed] [Google Scholar]
  29. Larrick J. W., Graham D., Toy K., Lin L. S., Senyk G., Fendly B. M. Recombinant tumor necrosis factor causes activation of human granulocytes. Blood. 1987 Feb;69(2):640–644. [PubMed] [Google Scholar]
  30. Larsen E., Celi A., Gilbert G. E., Furie B. C., Erban J. K., Bonfanti R., Wagner D. D., Furie B. PADGEM protein: a receptor that mediates the interaction of activated platelets with neutrophils and monocytes. Cell. 1989 Oct 20;59(2):305–312. doi: 10.1016/0092-8674(89)90292-4. [DOI] [PubMed] [Google Scholar]
  31. Lawrence M. B., Springer T. A. Leukocytes roll on a selectin at physiologic flow rates: distinction from and prerequisite for adhesion through integrins. Cell. 1991 May 31;65(5):859–873. doi: 10.1016/0092-8674(91)90393-d. [DOI] [PubMed] [Google Scholar]
  32. Ley K., Tedder T. F. Leukocyte interactions with vascular endothelium. New insights into selectin-mediated attachment and rolling. J Immunol. 1995 Jul 15;155(2):525–528. [PubMed] [Google Scholar]
  33. McEver R. P., Beckstead J. H., Moore K. L., Marshall-Carlson L., Bainton D. F. GMP-140, a platelet alpha-granule membrane protein, is also synthesized by vascular endothelial cells and is localized in Weibel-Palade bodies. J Clin Invest. 1989 Jul;84(1):92–99. doi: 10.1172/JCI114175. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. McEver R. P., Moore K. L., Cummings R. D. Leukocyte trafficking mediated by selectin-carbohydrate interactions. J Biol Chem. 1995 May 12;270(19):11025–11028. doi: 10.1074/jbc.270.19.11025. [DOI] [PubMed] [Google Scholar]
  35. Moore K. L., Eaton S. F., Lyons D. E., Lichenstein H. S., Cummings R. D., McEver R. P. The P-selectin glycoprotein ligand from human neutrophils displays sialylated, fucosylated, O-linked poly-N-acetyllactosamine. J Biol Chem. 1994 Sep 16;269(37):23318–23327. [PubMed] [Google Scholar]
  36. Moore K. L., Stults N. L., Diaz S., Smith D. F., Cummings R. D., Varki A., McEver R. P. Identification of a specific glycoprotein ligand for P-selectin (CD62) on myeloid cells. J Cell Biol. 1992 Jul;118(2):445–456. doi: 10.1083/jcb.118.2.445. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Morgan J. D., Lycett A., Horsburgh T., Nicholson M. L., Veitch P. S., Bell P. R. The importance of E-selectin as a marker for renal transplant rejection. Transpl Immunol. 1994 Dec;2(4):326–330. doi: 10.1016/0966-3274(94)90010-8. [DOI] [PubMed] [Google Scholar]
  38. Mulligan M. S., Polley M. J., Bayer R. J., Nunn M. F., Paulson J. C., Ward P. A. Neutrophil-dependent acute lung injury. Requirement for P-selectin (GMP-140). J Clin Invest. 1992 Oct;90(4):1600–1607. doi: 10.1172/JCI116029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Nadeau K. C., Azuma H., Tilney N. L. Sequential cytokine dynamics in chronic rejection of rat renal allografts: roles for cytokines RANTES and MCP-1. Proc Natl Acad Sci U S A. 1995 Sep 12;92(19):8729–8733. doi: 10.1073/pnas.92.19.8729. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Norman K. E., Moore K. L., McEver R. P., Ley K. Leukocyte rolling in vivo is mediated by P-selectin glycoprotein ligand-1. Blood. 1995 Dec 15;86(12):4417–4421. [PubMed] [Google Scholar]
  41. Palabrica T., Lobb R., Furie B. C., Aronovitz M., Benjamin C., Hsu Y. M., Sajer S. A., Furie B. Leukocyte accumulation promoting fibrin deposition is mediated in vivo by P-selectin on adherent platelets. Nature. 1992 Oct 29;359(6398):848–851. doi: 10.1038/359848a0. [DOI] [PubMed] [Google Scholar]
  42. Pinsky D. J., Naka Y., Liao H., Oz M. C., Wagner D. D., Mayadas T. N., Johnson R. C., Hynes R. O., Heath M., Lawson C. A. Hypoxia-induced exocytosis of endothelial cell Weibel-Palade bodies. A mechanism for rapid neutrophil recruitment after cardiac preservation. J Clin Invest. 1996 Jan 15;97(2):493–500. doi: 10.1172/JCI118440. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Pirsch J. D., Ploeg R. J., Gange S., D'Alessandro A. M., Knechtle S. J., Sollinger H. W., Kalayoglu M., Belzer F. O. Determinants of graft survival after renal transplantation. Transplantation. 1996 Jun 15;61(11):1581–1586. doi: 10.1097/00007890-199606150-00006. [DOI] [PubMed] [Google Scholar]
  44. Platzer C., Ode-Hakim S., Reinke P., Döcke W. D., Ewert R., Volk H. D. Quantitative PCR analysis of cytokine transcription patterns in peripheral mononuclear cells after anti-CD3 rejection therapy using two novel multispecific competitor fragments. Transplantation. 1994 Jul 27;58(2):264–268. [PubMed] [Google Scholar]
  45. Rabb H., Ramirez G., Saba S. R., Reynolds D., Xu J., Flavell R., Antonia S. Renal ischemic-reperfusion injury in L-selectin-deficient mice. Am J Physiol. 1996 Aug;271(2 Pt 2):F408–F413. doi: 10.1152/ajprenal.1996.271.2.F408. [DOI] [PubMed] [Google Scholar]
  46. Reinke P., Fietze E., Döcke W. D., Kern F., Ewert R., Volk H. D. Late acute rejection in long-term renal allograft recipients. Diagnostic and predictive value of circulating activated T cells. Transplantation. 1994 Jul 15;58(1):35–41. [PubMed] [Google Scholar]
  47. Rice G. E., Bevilacqua M. P. An inducible endothelial cell surface glycoprotein mediates melanoma adhesion. Science. 1989 Dec 8;246(4935):1303–1306. doi: 10.1126/science.2588007. [DOI] [PubMed] [Google Scholar]
  48. Sako D., Chang X. J., Barone K. M., Vachino G., White H. M., Shaw G., Veldman G. M., Bean K. M., Ahern T. J., Furie B. Expression cloning of a functional glycoprotein ligand for P-selectin. Cell. 1993 Dec 17;75(6):1179–1186. doi: 10.1016/0092-8674(93)90327-m. [DOI] [PubMed] [Google Scholar]
  49. Sako D., Comess K. M., Barone K. M., Camphausen R. T., Cumming D. A., Shaw G. D. A sulfated peptide segment at the amino terminus of PSGL-1 is critical for P-selectin binding. Cell. 1995 Oct 20;83(2):323–331. doi: 10.1016/0092-8674(95)90173-6. [DOI] [PubMed] [Google Scholar]
  50. Spertini O., Cordey A. S., Monai N., Giuffrè L., Schapira M. P-selectin glycoprotein ligand 1 is a ligand for L-selectin on neutrophils, monocytes, and CD34+ hematopoietic progenitor cells. J Cell Biol. 1996 Oct;135(2):523–531. doi: 10.1083/jcb.135.2.523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Subramaniam M., Saffaripour S., Watson S. R., Mayadas T. N., Hynes R. O., Wagner D. D. Reduced recruitment of inflammatory cells in a contact hypersensitivity response in P-selectin-deficient mice. J Exp Med. 1995 Jun 1;181(6):2277–2282. doi: 10.1084/jem.181.6.2277. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Vachino G., Chang X. J., Veldman G. M., Kumar R., Sako D., Fouser L. A., Berndt M. C., Cumming D. A. P-selectin glycoprotein ligand-1 is the major counter-receptor for P-selectin on stimulated T cells and is widely distributed in non-functional form on many lymphocytic cells. J Biol Chem. 1995 Sep 15;270(37):21966–21974. doi: 10.1074/jbc.270.37.21966. [DOI] [PubMed] [Google Scholar]
  53. Volk H. D., Müller S., Yarkoni S., Diamantstein T., Lorberboum-Galski H. Mechanisms of dichotomous action of IL-2-Pseudomonas exotoxin 40 (IL-2-PE40) on cell-mediated and humoral immune response. J Immunol. 1994 Sep 15;153(6):2497–2505. [PubMed] [Google Scholar]
  54. Weiser M. R., Williams J. P., Moore F. D., Jr, Kobzik L., Ma M., Hechtman H. B., Carroll M. C. Reperfusion injury of ischemic skeletal muscle is mediated by natural antibody and complement. J Exp Med. 1996 May 1;183(5):2343–2348. doi: 10.1084/jem.183.5.2343. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Weller A., Isenmann S., Vestweber D. Cloning of the mouse endothelial selectins. Expression of both E- and P-selectin is inducible by tumor necrosis factor alpha. J Biol Chem. 1992 Jul 25;267(21):15176–15183. [PubMed] [Google Scholar]
  56. Weller A., Isenmann S., Vestweber D. Cloning of the mouse endothelial selectins. Expression of both E- and P-selectin is inducible by tumor necrosis factor alpha. J Biol Chem. 1992 Jul 25;267(21):15176–15183. [PubMed] [Google Scholar]
  57. Weyrich A. S., Ma X. Y., Lefer D. J., Albertine K. H., Lefer A. M. In vivo neutralization of P-selectin protects feline heart and endothelium in myocardial ischemia and reperfusion injury. J Clin Invest. 1993 Jun;91(6):2620–2629. doi: 10.1172/JCI116501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Weyrich A. S., Ma X. Y., Lefer D. J., Albertine K. H., Lefer A. M. In vivo neutralization of P-selectin protects feline heart and endothelium in myocardial ischemia and reperfusion injury. J Clin Invest. 1993 Jun;91(6):2620–2629. doi: 10.1172/JCI116501. [DOI] [PMC free article] [PubMed] [Google Scholar]

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