Expression of urokinase plasminogen activator and its receptor during acute renal allograft rejection.
BACKGROUND
In inflammation, urokinase plasminogen activator (uPA) and its receptor (uPAR) play an important role in fibrinolysis and in activation and chemotaxis of neutrophils and lymphocytes. Moreover, the uPA/uPAR system is involved in processes that affect turnover of the extracellular matrix (ECM). The aim of this study was to determine the local and systemic release of uPAR, and the expression of uPA and uPAR in renal tissues during acute renal allograft rejection.


METHODS
Blood, urine, and tissue samples were collected from 33 patients diagnosed with acute allograft rejection and from 14 transplant patients without rejection. From 10 healthy volunteers, blood and urine were collected as a control. In urine and blood samples, the levels of uPAR were determined by enzyme-linked immunosorbent assay (ELISA). Immunostaining and in situ hybridization for uPA and uPAR were performed on renal biopsies.


RESULTS
uPAR was detectable at low levels in serum and urine of healthy volunteers and was increased in nonrejecting allograft recipients. Serum and urine levels of uPAR were higher in transplant recipients with rejection compared to nonrejectors. The urine and serum levels of uPAR correlated with the renal function. Immunostaining and in situ hybridization showed an up-regulation of both uPA and uPAR in rejection biopsies. Nonrejected grafts displayed no expression of uPA and uPAR by immunostaining, or of uPAR by in situ hybridization. uPA was detected in a limited number of tubular epithelial cells by in situ hybridization. During rejection, lymphocytes as well as tubular epithelial cells showed uPA and uPAR expression. In the vascular types of rejection, strong expression of uPA was also seen in the entire vessel wall, while uPAR was expressed by the endothelium.


CONCLUSIONS
This study shows that (1) uPA and uPAR are up-regulated during acute renal allograft rejection; (2) uPAR levels in urine and serum correlate with serum creatinine levels, and (3) uPA and uPAR are produced by inflammatory cells, tubular epithelium, and vascular endothelium during acute renal allograft rejection.
Roelofs
Joris J T H
JJ
Department of Pathology and Renal Transplant Unit, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. j.j.roelofs@amc.uva.nl
Rowshani
Ajda T
AT
van den Berg
José G
JG
Claessen
Nike
N
Aten
Jan
J
ten Berge
Ineke J M
IJ
Weening
Jan J
JJ
Florquin
Sandrine
S
D000208:Acute Disease; D000328:Adult; D005260:Female; D015870:Gene Expression; D006084:Graft Rejection / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D011956:Receptors, Cell Surface / Q000235:genetics*; D055293:Receptors, Urokinase Plasminogen Activator; D014184:Transplantation, Homologous; D014568:Urokinase-Type Plasminogen Activator / Q000097:blood / Q000235:genetics* / Q000652:urine
C524898:PLAUR protein, human; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator