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Renal Urokinase-Type Plasminogen Activator (uPA) Receptor but not uPA Deficiency Strongly Attenuates Ischemia Reperfusion Injury and Acute Kidney Allograft Rejection

Faikah Gueler^1,*, Song Rong^1,*, Michael Mengel, Joon-Keun Park^*, Julia Kiyan^*, Torsten Kirsch^*, Inna Dumler^*, Hermann Haller^* and Nelli Shushakova^2,*,

^* Department of Nephrology and Department of Pathology, Medical School Hannover, Hannover, Germany; and Phenos GmbH, Hannover, Germany

Central mechanisms leading to ischemia induced allograft rejection are apoptosis and inflammation, processes highly regulated by the urokinase-type plasminogen activator (uPA) and its specific receptor (uPAR). Recently, up-regulation of uPA and uPAR has been shown to correlate with allograft rejection in human biopsies. However, the causal connection of uPA/uPAR in mediating transplant rejection and underlying molecular mechanisms remain poorly understood. In this study, we evaluated the role of uPA/uPAR in a mice model for kidney ischemia reperfusion (IR) injury and for acute kidney allograft rejection. uPAR but not uPA deficiency protected from IR injury. In the allogenic kidney transplant model, uPAR but not uPA deficiency of the allograft caused superior recipient survival and strongly attenuated loss of renal function. uPAR-deficient allografts showed reduced generation of reactive oxygen species and apoptosis. Moreover, neutrophil and monocyte/macrophage infiltration was strongly attenuated and up-regulation of the adhesion molecule ICAM-1 was completely abrogated in uPAR-deficient allografts. Inadequate ICAM-1 up-regulation in uPAR^–/– primary aortic endothelial cells after C5a and TNF- stimulation was confirmed by in vitro experiments. Our results demonstrate that the local renal uPAR plays an important role in the apoptotic and inflammatory responses mediating IR-injury and transplant rejection.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ F.G. and S.R. contributed equally to this work.

² Address correspondence and reprint requests to Dr. Nelli Shushakova, Nephrology Department, Hannover Medical School, Carl-Neuberg Strasse 1, D-30625 Hannover, Germany. E-mail address: nshushakova{at}phenos.com

³ Abbreviations used in this paper: uPA, urokinase-type plasminogen activator; uPAR, urokinase-type plasminogen activator receptor; IR, ischemia reperfusion; ROS, reactive oxygen species; RT, room temperature; DHE, dihydroethidium; PFA, paraformaldehyde; MAEC, mouse aortic endothelial cell; PBMC, peripheral blood mononuclear cell; MO, monocytes/macrophages; PMN, polymorphonuclear leukocyte; ATN, acute tubular necrosis; C5aR, receptor for C5a anaphylatoxin; MO, macrophage/monocyte; WT, wild type.