title: Prevention of late renal changes after initial ischemia/reperfusion injury by blocking early selectin binding.
abstract: BACKGROUND
  Increasing clinical evidence suggests that delayed initial function secondary to ischemia/reperfusion injury alone, and particularly in combination with early episodes of acute rejection, reduces kidney allograft survival over time.
  
  
  METHODS
  We investigated changes developing over the long term following a standardized ischemia/reperfusion insult in a Lewis rat model. The left kidney was isolated in a uninephrectomized host and cooled, and the pedicle was clamped for 45 min. Animals were followed for 48 weeks after initial renal injury. Organs were removed serially (4, 8, 16, 24, 32, 40, and 48 weeks) for immunohistology and reverse transcriptase polymerase chain reaction.
  
  
  RESULTS
  Progressive proteinuria developed after 8 weeks. By immunohistology, CD4+ leukocytes and ED-1+ macrophages infiltrated the ischemic organs in parallel with up-regulation of major histocompatibility complex class II antigen expression. Because macrophages have been shown to be critical in chronic changes in other models, they were examined primarily in these studies. By reverse transcriptase polymerase chain reaction, macrophage-derived, fibrosis-inducing factors (transforming growth factor-beta, interleukin 6, and tumor necrosis factor-alpha) remained highly and constantly expressed throughout the follow-up period. The long-term influence of initial treatment with the soluble form of P-selectin glycoprotein ligand-1, a soluble ligand for P- and E-selectin, was then examined. All functional and structural changes remained at relative baseline, similar to uninephrectomized controls.
  
  
  CONCLUSIONS
  These data suggest that blocking the initial selectin-mediated step after ischemia/reperfusion injury, which triggers significant early cellular and molecular events, also reduces later renal dysfunction and tissue damage over time. In part, the findings may be explained by the sparing of functioning nephron units, which if destroyed or compromised by the original insult, may contribute to long-term graft failure. This approach may be important clinically in the transplantation of kidneys from non-heart-beating or marginal donors or organs experiencing prolonged ischemic times.
authors.affiliation: Harvard Medical School, and Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: M
authors.initials: M
authors.lastname: Takada
authors.forename: K C
authors.initials: KC
authors.lastname: Nadeau
authors.forename: G D
authors.initials: GD
authors.lastname: Shaw
authors.forename: N L
authors.initials: NL
authors.lastname: Tilney
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000096:biosynthesis; D019332:Endothelin-1 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D007511:Ischemia / Q000473:pathology*; D007668:Kidney / Q000098:blood supply* / Q000473:pathology; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009077:Mucins / Q000378:metabolism*; D019007:P-Selectin / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011507:Proteinuria / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D018932:Chemokine CCL2; D019332:Endothelin-1; D015850:Interleukin-6; D008024:Ligands; D008562:Membrane Glycoproteins; D009077:Mucins; D019007:P-Selectin; C084882:P-selectin ligand protein; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha