Type i interferon pathway mediates renal ischemia/reperfusion injury

Maria Cecilia S. Freitas, Yoichiro Uchida, Charles Lassman, Gabriel M. Danovitch, Ronald W. Busuttil, Jerzy W. Kupiec-Weglinski

Research output: Contribution to journalArticlepeer-review

31 Citations (Scopus)

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. Conclusion. 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.

Original languageEnglish
Pages (from-to)131-138
Number of pages8
JournalTransplantation
Volume92
Issue number2
DOIs
Publication statusPublished - 27-07-2011
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Transplantation

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