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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. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-03-008870v1 109/2/577    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Sevastos, J. Articles by Erlich, J. H. Search for Related Content PubMed PubMed Citation Articles by Sevastos, J. Articles by Erlich, J. H. Related Collections Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Tissue factor deficiency and PAR-1 deficiency are protective against renal ischemia reperfusion injury Jacob Sevastos1,2, Sean E. Kennedy1,2, Darren R. Davis1, Melissa Sam1,2, Philip W. Peake2, John A. Charlesworth1,2, Nigel Mackman3,4, and Jonathan H. Erlich1,2, 1 Prince of Wales Clinical School, University of New South Wales (NSW), Sydney, Australia; 2 Department of Nephrology, Prince of Wales Hospital, Randwick, NSW, Australia; 3 Department of Immunology, Scripps Research Institute, La Jolla, CA; 4 Department Cell Biology, Scripps Research Institute, La Jolla, CA Ischemia/reperfusion (IR) injury is a leading cause of acute renal failure and an important contributor to allograft damage. Tissue factor (TF) is up-regulated 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 by production of coagulation proteases and subsequent signaling 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 up-regulation 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 by thrombin-dependent PAR-1 signaling. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. L. Strande Letter by Strande Regarding Article "Protease-Activated Receptor-1 Contributes to Cardiac Remodeling and Hypertrophy" Circulation, June 17, 2008; 117(24): e495 - e495. [Full Text] [PDF] R. A. Schuepbach, C. Feistritzer, L. F. Brass, and M. Riewald Activated protein C-cleaved protease activated receptor-1 is retained on the endothelial cell surface even in the presence of thrombin Blood, March 1, 2008; 111(5): 2667 - 2673. [Abstract] [Full Text] [PDF] P. Redecha, R. Tilley, M. Tencati, J. E. Salmon, D. Kirchhofer, N. Mackman, and G. Girardi Tissue factor: a link between C5a and neutrophil activation in antiphospholipid antibody induced fetal injury Blood, October 1, 2007; 110(7): 2423 - 2431. [Abstract] [Full Text] [PDF] C. Anthoni, J. Russell, K. C. Wood, K. Y. Stokes, T. Vowinkel, D. Kirchhofer, and D. N. Granger Tissue factor: a mediator of inflammatory cell recruitment, tissue injury, and thrombus formation in experimental colitis J. Exp. Med., July 9, 2007; 204(7): 1595 - 1601. [Abstract] [Full Text] [PDF]

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