Expression of urokinase plasminogen activator and its receptor during acute renal allograft rejection

Roelofs, Joris J. T. H.; Rowshani, Ajda T.; Berg, José G. van den; Claessen, Nike; Aten, Jan; Berge, Ineke J. M. ten; Weening, Jan J.; Florquin, Sandrine

doi:10.1046/j.1523-1755.2003.00261.x

Cited by 37 publications

(34 citation statements)

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“…The uPAR colocalizes with uPA at focal contacts in the leading edge of migrating cells (26). The uPAR has now been identified on a variety of other cell types, including inflammatory cells (monocytes, macrophages, neutrophils, activated T cells), vascular endothelial cells, epithelial cells (both glomerular and tubular), mesenchymal cells (fibroblasts, myofibroblasts, mesangial cells), and neurons (23,(27)(28)(29)(30)(31)(32). The uPAR, a highly glycosylated 50-kD to 65-kD protein, is a transmembrane receptor with three extracellular domains (D1, D2 and D3) and a single membrane-inserted domain connected to a very short glycosyl-phosphatidylinositol (GPI)-anchored cytoplasmic tail.…”

Section: Functional Overviewmentioning

confidence: 99%

“…However, de novo expression by glomerular and tubular epithelial cells and a variety of renal interstitial cells (fibroblasts, inflammatory cells and endothelial cells) has been confirmed in human renal diseases such as diabetic nephropathy, allograft rejection and pyelonephritis (29,44,45). There is a growing list of uPAR agonists that include interleukins-1, -2, -4, -6, -7, -10, -13; tumor necrosis factor-α and -β; TGF-β; interferon-α, -γ; thrombospondin-1 and monocyte chemoattractant proteins-1, -2, -3 (46-48).…”

Section: Upar In Experimental Kidney Diseasementioning

confidence: 99%

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Urokinase and its receptors in chronic kidney disease

Zhang

Eddy

2008

Front Biosci

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Since the recognition that plasminogen activator inhibitor-1 (PAI-1) is a powerful profibrotic molecule, there has been considerable interest in deciphering the extent to which this effect is mediated by its ability to inhibit serine proteases with downstream effects on fibrogenesis. This review will summarize current knowledge about the serine protease urokinase-type plasminogen activator and its high affinity receptor uPAR/CD87 as it pertains to chronic kidney disease (CKD) progression. An emerging theme is that the effects of PAI-1 and uPAR appear to be organ-and site-specific. Normal kidney tubules produce a large quantity of uPA that is secreted into the urinary space. Activity levels increase during CKD presumably due to new sources of production by macrophages and fibroblasts. By activating hepatocyte growth factor and degrading fibrinogen uPA may have anti-fibrotic effects. However CKD severity after experimental ureteral obstruction is not altered by endogenous uPA deficiency. Beneficial effects of exogenous uPA have been reported in experimental models of fibrosis in the lung and liver but CKD awaits exploration.Absent in normal kidneys uPAR is expressed by both renal parenchymal cells and inflammatory cells in a variety of pathological states. Such expression appears beneficial based on studies performed in uPAR-deficient mice. The uPAR promotes bacterial clearance in infectious diseases. In CKD uPAR expression is associated with high uPA activity but its most important effect appears to be due to scavenging activities and effects on cell recruitment and migration. Although uPAR itself is a non-signaling receptor, it interacts with a variety of co-receptors to modify cellular behavior. Best known are interactions with the low-density lipoprotein receptor-related protein (LRP-1) that lead to PAI-1 endocytosis and degradation, and interactions with several integrins to regulate matrix-dependent cell migration. Contacts with the receptor for the complement C5a component and the interleukin −6 receptor gp130 are examples of other recently recognized interactions.In addition to uPA, vitronectin and high molecular weight kininogen are alternate uPAR ligands that could be implicated in CKD progression. uPAR may also be shed from cell membranes. This soluble form (suPAR) has been detected in plasma and urine and is known to be a chemoattractant for leukocytes that express the formyl-peptide-receptor-like receptor

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Section: Functional Overviewmentioning

confidence: 99%

Section: Upar In Experimental Kidney Diseasementioning

confidence: 99%

Urokinase and its receptors in chronic kidney disease

Zhang

Eddy

2008

Front Biosci

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“…The underlined primer regions encode the T7-promotor element. Using the probe, in situ hybridization was performed, as described previously (18), using the digoxigenin-labeled riboprobes at a concentration of 300 ng/ml. After hybridization, slides were washed, and bound alkaline phosphatase activity was visualized with NBT chloride and 5-bromo-4-chloro-3-indolylphosphate, toluidine salt (Roche).…”

Section: In Situ Hybridizationmentioning

confidence: 99%

Matrix Metalloproteinase-9 Deficiency Impairs Host Defense against Abdominal Sepsis

Renckens¹,

Roelofs²,

Florquin³

et al. 2006

The Journal of Immunology

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109

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Matrix metalloproteinase (MMP)-9 is involved in extracellular matrix degradation and leukocyte migration. To determine the role of MMP-9 in the innate immune response to peritonitis, MMP-9 gene-deficient (MMP-9−/−) and normal wild-type mice were i.p. infected with Escherichia coli. MMP-9 mRNA and pro-MMP-9 protein levels increased rapidly upon induction of peritonitis. Although MMP-9−/− neutrophils showed a normal phagocytosis of E. coli in vitro, MMP-9−/− mice displayed a reduced resistance against E. coli peritonitis, as indicated by an enhanced bacterial outgrowth in the peritoneal cavity and increased dissemination of the infection. Furthermore, the cytokine response to LPS was not influenced by MMP-9 deficiency. However, during E. coli peritonitis, MMP-9−/− mice showed much higher peritoneal chemokine and cytokine levels compared with wild-type mice. Despite the increased local chemokine concentrations, MMP-9−/− mice displayed a diminished recruitment of leukocytes to the site of infection, indicating that cellular migration was impaired. Moreover, MMP-9−/− mice developed more severe distant organ damage during infection. These data suggest that MMP-9 is an essential component of an effective host response to E. coli peritonitis.

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“…The underlined primer regions encode the T7-promoter element. Using these probes, in situ hybridization was performed as described previously (18), using the digoxigenin-labeled riboprobes at a concentration of 300 ng/ml. After hybridization, slides were washed and bound alkaline phosphatase activity was visualized with NBT chloride and 5-bromo-4-chloro-3-indolylphosphate (BCIP), toluidine salt (NBT/BCIP) (Roche).…”

Section: In Situ Hybridizationmentioning

confidence: 99%

Endogenous Tissue-Type Plasminogen Activator Is Protective duringEscherichia coli-Induced Abdominal Sepsis in Mice

Renckens

Roelofs

Florquin

et al. 2006

The Journal of Immunology

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Sepsis is associated with enhanced production of tissue-type plasminogen activator (tPA). We investigated the function of endogenous tPA in the immune responses to Escherichia coli-induced abdominal sepsis using tPA gene-deficient (tPA−/−) and normal wild-type (WT) mice. tPA−/− mice demonstrated an impaired defense against E. coli peritonitis as indicated by higher bacterial loads at the primary site of the infection, enhanced dissemination, and reduced survival. The protective function of tPA was independent of plasmin since plasminogen gene-deficient (Plg−/−) mice were indistinguishable from WT mice. Relative to WT mice, tPA−/− mice demonstrated similar neutrophil counts in the peritoneal cavity despite much higher bacterial loads and higher local concentrations of neutrophil attracting chemokines, suggesting a reduced migratory response. In line, tPA−/− mice demonstrated a reduced thioglycolate-induced neutrophil influx into the peritoneal cavity and i.p. injection of WT mice with a replication-defective adenoviral vector expressing tPA caused an enhanced cell migration to the peritoneal cavity during E. coli peritonitis. These findings identify a novel protective function of tPA in abdominal sepsis caused by E. coli that seems independent of its role in the generation of plasmin.

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Expression of urokinase plasminogen activator and its receptor during acute renal allograft rejection

Cited by 37 publications

References 50 publications

Urokinase and its receptors in chronic kidney disease

Urokinase and its receptors in chronic kidney disease

Matrix Metalloproteinase-9 Deficiency Impairs Host Defense against Abdominal Sepsis

Endogenous Tissue-Type Plasminogen Activator Is Protective duringEscherichia coli-Induced Abdominal Sepsis in Mice

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