Renal urokinase-type plasminogen activator (uPA) receptor but not uPA deficiency strongly attenuates ischemia reperfusion injury and acute kidney allograft rejection.
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-alpha 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.
Gueler
Faikah
F
Department of Nephrology, Medical School Hannover, Hannover, Germany.
Rong
Song
S
Mengel
Michael
M
Park
Joon-Keun
JK
Kiyan
Julia
J
Kirsch
Torsten
T
Dumler
Inna
I
Haller
Hermann
H
Shushakova
Nelli
N
D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D006084:Graft Rejection; D006085:Graft Survival; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism; D007668:Kidney / Q000098:blood supply / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D051379:Mice; D020556:Neutrophil Infiltration; D017382:Reactive Oxygen Species / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator; D015427:Reperfusion Injury / Q000276:immunology / Q000378:metabolism*; D014184:Transplantation, Homologous; D015854:Up-Regulation; D014568:Urokinase-Type Plasminogen Activator / Q000172:deficiency / Q000378:metabolism
C090509:Icam1 protein, mouse; C524898:PLAUR protein, human; C524899:Plaur protein, mouse; D017382:Reactive Oxygen Species; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D018799:Intercellular Adhesion Molecule-1; D014568:Urokinase-Type Plasminogen Activator