Renal urokinase-type plasminogen activator (uPA) receptor but not uPA deficiency strongly attenuates ischemia reperfusion injury and acute kidney allograft rejection.

Department of Nephrology, Medical School Hannover, Hannover, Germany.
The Journal of Immunology (Impact Factor: 5.52). 08/2008; 181(2):1179-89.
Source: PubMed

ABSTRACT 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.

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    ABSTRACT: PURPOSE: The plasminogen system plays many roles in normal epithelial cell function, and components are elevated in diseases, such as cancer and asthma. The relative contribution of each component to epithelial function is unclear. We characterized normal cell function in airway epithelial cells with increased expression of selected pathway components. METHODS: BEAS-2B R1 bronchial epithelial cells stably overexpressing membrane urokinase plasminogen activator receptor (muPAR), soluble spliced uPAR (ssuPAR), the ligand (uPA) or inhibitors (PAI1 or PAI2), were characterized for pathway expression. Cell function was examined using proliferation, apoptosis, and scratch wound assays. A549 alveolar epithelial cells overexpressing muPAR were similarly characterized and downstream plasmin activity, MMP-1, and MMP-9 measured. RESULTS: Elevated expression of individual components led to changes in the plasminogen system expression profile, indicating coordinated regulation of the pathway. Increased muPAR expression augmented wound healing rate in BEAS-2B R1 and attenuated repair in A549 cells. Elevated expression of other system components had no effect on cell function in BEAS-2B R1 cells. This is the first study to investigate activity of the splice variant ssuPAR, with results suggesting that this variant plays a limited role in epithelial cell function in this model. CONCLUSIONS: Our data highlight muPAR as the critical molecule orchestrating effects of the plasminogen system on airway epithelial cell function. These data have implications for diseases, such as cancer and asthma, and suggest uPAR as the key therapeutic target for the pathway in approaches to alter epithelial cell function.
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    ABSTRACT: Renal ischemia reperfusion injury leads to acute kidney injury (AKI) and is associated with tissue edema, inflammatory cell infiltration, and subsequent development of interstitial renal fibrosis and tubular atrophy. The purpose of this study was to investigate the value of the functional magnetic resonance imaging (MRI) techniques, T2 mapping, and diffusion-weighted imaging (DWI) in characterizing acute and chronic pathology after unilateral AKI in mice. Moderate or severe AKIs were induced in C57Bl/6 mice through transient unilateral clamping of the renal pedicle for 35 minutes (moderate AKI) or 45 minutes (severe AKI), respectively. Magnetic resonance imaging was performed in 10 animals with moderate AKI and 7 animals with severe AKI before surgery and at 5 time points thereafter (days 1, 7, 14, 21, 28) using a 7-T magnet. Fat-saturated T2-weighted images, multiecho turbo spin echo, and diffusion-weighed sequences (7 b values) were acquired in matching coronal planes. Parameter maps of T2 relaxation time and apparent diffusion coefficient (ADC) were calculated, and mean values were determined for the renal cortex, the outer medulla, and the inner medulla. Inflammatory cell infiltration with monocytes/macrophages (F4/80), T-lymphocytes (CD4, CD8), and dendritic cells (CD11c) as well as the degree of interstitial fibrosis 4 weeks after AKI were determined through renal histology and immunohistochemistry. Statistical analysis comprised unpaired t tests for group comparisons and correlation analysis between MRI parameters and kidney volume loss. Increase of T2 relaxation time, indicating tissue edema, was most pronounced in the outer medulla and reached maximum values at d7 after AKI. At this time point, T2 values in the outer medulla were significantly increased to 53.8 ± 2.5 milliseconds after the severe AKI and to 46.3 ± 2.3 milliseconds after the moderate AKI when compared with the respective contralateral normal kidneys (40.9 ± 0.9 and 36.4 ± 1.2 milliseconds, respectively; P < 0.01). The T2 values reached baseline by d28. Medullary ADC was significantly reduced at all time points after AKI; restriction of diffusion was significantly more pronounced after the severe AKI than after the moderate AKI at d14 and d28. Changes of renal T2 and ADC values were associated with the severity of AKI as well as the degree of inflammatory cell infiltration and interstitial renal fibrosis 4 weeks after AKI. Furthermore, relative changes of both MRI parameters significantly correlated with kidney volume loss 4 weeks after AKI. Measuring T2 and ADC values through MRI is a noninvasive way to determine the presence and severity of acute and chronic renal changes after AKI in mice. Thus, the method should prove useful in animal and human clinical studies.
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    The Korean Journal of Internal Medicine 03/2014; 29(2):166-9.

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