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Blood, 15 January 2007, Vol. 109, No. 2, pp. 577-583.
Prepublished online as a Blood First Edition Paper on September 21, 2006; DOI 10.1182/blood-2006-03-008870.
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Submitted March 30, 2006
Accepted August 22, 2006
Tissue factor deficiency and PAR-1 deficiency are protective against renal ischaemia reperfusion injury
Jacob Sevastos, Sean E Kennedy, Darren R Davis, Melissa Sam, Philip W Peake, John A Charlesworth, Nigel Mackman, and Jonathan H Erlich*
Prince of Wales Clinical School, University of New South Wales, Australia
Dept of Nephrology, Prince of Wales Hospital, Randwick, Australia
Scripps Research Institute, Depts of Immunology and Cell Biology, La Jolla, CA
* Corresponding author; email: j.erlich{at}unsw.edu.au.
Ischemia/reperfusion (IR) injury is a leading cause of acute renal failure and an important contributor to allograft damage. Tissue factor (TF) is upregulated during IR and TF inhibition reduces renal injury. However, the underlying mechanisms by which TF contributes to injury have not been elucidated. We postulated that TF contributes to IR injury via production of coagulation proteases and subsequent signalling by protease activated receptor (PARs). We compared renal injury after 25 minutes of bilateral renal ischemia and varying periods of reperfusion in C57BL/6 mice, those expressing low levels of TF (low-TF), hirudin-treated C57BL/6 and mice lacking either PAR-1 or PAR-2. C57BL/6 mice developed severe renal failure and died within 48 hours of reperfusion. In contrast, low-TF, hirudin-treated C57BL/6, and PAR-1-/- mice were protected from renal failure and had reduced mortality, tubular injury, neutrophil accumulation, and lower levels of the chemokines KC and MIP-2. Importantly, PAR-1-/- mice had lower chemokine levels despite upregulation of TF and fibrin deposition. In addition, treating PAR-1-/- mice with hirudin conferred no additional benefit. Somewhat surprisingly, PAR-2 deficiency did not protect from renal failure. These experiments indicate that increased TF activity after renal IR leads to increased CXC chemokine expression and subsequent neutrophil mediated injury predominantly via thrombin-dependent PAR-1 signalling.
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