title: Type I interferon pathway mediates renal ischemia/reperfusion injury.
abstract: BACKGROUND
  Ischemia/reperfusion (I/R) injury is a common cause of acute renal failure after kidney transplantation. This study was designed to analyze the role of type I interferon (IFN) signaling downstream of Toll-like receptor 2/Toll-like receptor 4 activation in the mechanism of I/R-triggered kidney damage.
  
  
  METHODS
  Local warm ischemia was induced in groups wild-type (WT) and type I IFN receptor (IFNAR)-/- mice (C57BL/6) by clamping both kidney pedicles for 45 min. Mice were killed at 5/24/72 hr after reperfusion for serum and kidney sampling.
  
  
  RESULTS
  At 5 hr, serum creatinine and blood urea nitrogen levels were markedly reduced in IFNAR-/- mice as compared with WT. By 24 hr after reperfusion, both serum creatinine/blood urea nitrogen in WT increased further, whereas those in IFNAR-/- mice remained comparable with sham controls. Histological analyses showed significantly higher percentage of tubules in the outer medulla displaying cell necrosis, loss of the brush border, cast formation and tubular dilatation in WT mice, as compared with IFNAR-/-. Immunohistology revealed increased neutrophil and macrophage infiltration in the outer medulla in WT mice. The expression of proinflammatory tumor necrosis factor-α, interleukin-1, interleukin-6, and CXCL-2 was markedly reduced selectively in IFNAR-/- mice. Finally, terminal deoxynucleotide transferase-mediated dUTP nick-end labeling analysis showed significantly decreased frequency of apoptotic tubular epithelial cells in IFNAR-deficient mice, as compared with WT.
  
  
  CONCLUSIONS
  This is the first report, which documents the key role of type I IFN signaling in the mechanism of kidney I/R injury. Type I IFN may thus serve as a novel target for the therapy against renal I/R injury.
authors.affiliation: Division of Liver and Pancreas Transplantation, Department of Surgery, Dumont-UCLA Transplant Center, Los Angeles, CA 90095, USA.
authors.forename: Maria Cecilia S
authors.initials: MC
authors.lastname: Freitas
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Uchida
authors.forename: Charles
authors.initials: C
authors.lastname: Lassman
authors.forename: Gabriel M
authors.initials: GM
authors.lastname: Danovitch
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Busuttil
authors.forename: Jerzy W
authors.initials: JW
authors.lastname: Kupiec-Weglinski
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood; D016207:Cytokines / Q000378:metabolism; D007370:Interferon Type I / Q000502:physiology*; D007668:Kidney / Q000098:blood supply* / Q000473:pathology / Q000503:physiopathology*; D007679:Kidney Medulla / Q000473:pathology; D016030:Kidney Transplantation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D015427:Reperfusion Injury / Q000473:pathology / Q000503:physiopathology*; D015398:Signal Transduction / Q000502:physiology*; D051195:Toll-Like Receptor 2 / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000502:physiology
chemical_list: D016207:Cytokines; D007370:Interferon Type I; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D053633:Receptor, Interferon alpha-beta; D003404:Creatinine