Full-length soluble urokinase plasminogen activator receptor down-modulates nephrin expression in podocytes.
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ABSTRACT:
SUBMITTER: Alfano M
PROVIDER: S-EPMC4585377 | biostudies-other | 2015
REPOSITORIES: biostudies-other
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Project description:PurposeOur previous study revealed the immunomodulatory property of the secreted lymphocyte antigen (Ly6)/urokinase-type plasminogen activator receptor (uPAR)-related protein-1 (SLURP1), abundantly expressed in the cornea and associated with the hyperkeratotic disorder Mal de Meleda. Here, we test the hypothesis that SLURP1 modulates the functions of membrane-tethered uPAR by acting as a soluble scavenger of its ligand urokinase-type plasminogen activator (uPA).MethodsHuman corneal limbal epithelial (HCLE) and mouse corneal stromal fibroblast MK/T-1 cells were employed to examine the effect of SLURP1 on cell proliferation and migration. Human corneal limbal epithelial cell clones stably expressing SLURP1 under the control of cytomegalovirus (CMV) promoter were generated using lentiviral vectors. Recombinant 6× His-mouse Slurp1 and maltose-binding protein (MBP)-mouse uPA were expressed in Escherichia coli and partially purified using nickel-ion and amylose columns, respectively. Slurp1 interaction with uPA was detected using ligand blots, ELISA, pull-down assays, and immunofluorescent staining.ResultsStable expression of SLURP1 in HCLE cells was confirmed by immunoblots and immunofluorescent staining. Human corneal limbal epithelial and MK/T-1 cell proliferation and migration rates were suppressed by exogenous SLURP1. Ligand blots, ELISA, and pull-down assays indicated that Slurp1 efficiently interacts with uPA. Immunofluorescent staining demonstrated that exogenous SLURP1 decreased the amount of cell surface-bound uPA in the leading edges of migrating cells. In gap-filling assays, wild-type HCLE cells responded to uPA by increasing their velocity and closing larger area, while the SLURP1-expressing HCLE cells failed to do so.ConclusionsSLURP1 modulates corneal homeostasis by serving as a soluble scavenger of uPA and regulating the uPA-dependent functions of uPAR.
| S-EPMC4183074 | biostudies-literature
Project description:BACKGROUND:The inflammatory biomarker soluble urokinase plasminogen activator receptor (suPAR) is elevated in severe acute and chronic medical conditions and has been associated with short-term mortality. The role of suPAR in predicting risk of death following an acute exacerbation of chronic obstructive pulmonary disease (AECOPD) has never been studied. We hypothesized that increased suPAR is an independent predictor of short-term mortality in patients admitted to hospital with COPD or acute respiratory failure. METHODS:This retrospective cohort study from a university hospital in the Capital Region of Denmark included 2838 acutely admitted medical patients with COPD as primary (AECOPD) or secondary diagnosis, who had plasma suPAR measured at the time of admission between November 18th, 2013 to September 30th, 2015 and followed until December 31st, 2015. Primary outcomes were 30- and 90-days all-cause mortality. Association of suPAR and mortality was investigated by Cox regression analyses adjusted for age, sex, CRP values and Charlson comorbidity index. RESULTS:For patients with AECOPD or underlying COPD, median suPAR levels were significantly higher among patients who died within 30 days compared with those who survived (5.7 ng/ml (IQR 3.8-8.1) vs. 3.6 ng/ml (2.7-5.1), P <?0.0001). Increasing suPAR levels independently predicted 30-day mortality in patients with COPD with a hazard ratio of 2.0 (95% CI 1.7-2.4) but not respiratory failure. CONCLUSIONS:In this large group of acutely admitted patients with COPD, elevated suPAR levels were associated with increased risk of mortality. The study supports the value of suPAR as a marker of poor prognosis.
| S-EPMC5963104 | biostudies-literature
Project description:Eosinophils migrate from the vascular circulation to the inflamed airways during asthma exacerbations. While the mechanism(s) of this process is not known, the expression of urokinase-type plasminogen activator receptor (uPAR) has been found to modulate neutrophil adhesion and migration to inflammatory sites. We hypothesized that increased expression of uPAR and its ligand, uPA, enhance eosinophil adhesion in patients with asthma. Patients with allergic asthma underwent segmental bronchoprovocation with allergen; 48 h later, peripheral blood and airway (from bronchoalveolar lavage fluid) eosinophils were isolated. uPA and uPAR protein expression were measured by flow cytometry and Western blot; mRNA was quantified by real-time PCR. Eosinophil adhesion to intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 was assessed by eosinophil peroxidase activity. Airway eosinophils expressed significantly more uPA and uPAR protein and uPAR mRNA than peripheral blood eosinophils. Removal of cell-bound uPA and/or addition of exogenous uPA had no effect on blood eosinophil adhesion to ICAM-1 or VCAM-1. In contrast, exogenous uPA stimulated ICAM and VCAM adhesion of airway eosinophils. N-formyl-methionyl-leucyl-phenylalanine-activated airway eosinophil adherence to VCAM-1 and ICAM-1 (VCAM-1, 52.8 +/- 4.7%; ICAM-1, 49.2 +/- 5.3%) was increased over blood eosinophil adhesion (VCAM-1, 38.4 +/- 3.6%; ICAM-1, 27.7 +/- 4.9%; P < 0.05). Removal of cell-bound uPA from airway eosinophils decreased adhesion to blood cell levels; reintroduction of exogenous uPA completely restored adhesion levels. These data suggest that constitutive uPA primes, and exogenous uPA can activate, airway eosinophil adhesion following segmental allergen challenge and that increased uPA expression may be a mechanism of increased eosinophil infiltration and function in asthma.
| S-EPMC2643268 | biostudies-literature
Project description:Background and Objectives: Obstructive sleep apnoea (OSA) is associated with heightened systemic inflammation and a hypercoagulation state. Soluble urokinase-type plasminogen activator receptor (suPAR) plays a role in fibrinolysis and systemic inflammation. However, suPAR has not been investigated in OSA. Materials and Methods: A total of 53 patients with OSA and 15 control volunteers participated in the study. Medical history was taken and in-hospital sleep studies were performed. Plasma suPAR levels were determined by ELISA. Results: There was no difference in plasma suPAR values between patients with OSA (2.198 ± 0.675 ng/mL) and control subjects (2.088 ± 0.976 ng/mL, p = 0.62). Neither was there any difference when patients with OSA were divided into mild (2.134 ± 0.799 ng/mL), moderate (2.274 ± 0.597 ng/mL) and severe groups (2.128 ± 0.744 ng/mL, p = 0.84). There was no significant correlation between plasma suPAR and indices of OSA severity, blood results or comorbidities, such as hypertension, diabetes, dyslipidaemia or cardiovascular disease. Plasma suPAR levels were higher in women when all subjects were analysed together (2.487 ± 0.683 vs. 1.895 ± 0.692 ng/mL, p < 0.01), and also separately in controls (2.539 ± 0.956 vs. 1.411 ± 0.534 ng/mL, p = 0.02) and patients (2.467 ± 0.568 vs. 1.991 ± 0.686 ng/mL, p < 0.01). Conclusions: Our results suggest that suPAR does not play a significant role in the pathophysiology of OSA. The significant gender difference needs to be considered when conducting studies on circulating suPAR.
| S-EPMC7074407 | biostudies-literature
Project description:BackgroundThe soluble urokinase plasminogen activator receptor (suPAR) is related to hepatic inflammation and fibrosis and has been suggested to participate in the development of liver cirrhosis. Therefore, the aim of the current study was to measure the concentration of suPAR in the hepatic vein of cirrhotic patients during a liver vein catheterization to identify a possible hepatic suPAR generation. Furthermore, we explored if suPAR levels were associated with the degree of cirrhosis and liver dysfunction.Methods and patientsWe included 105 cirrhotic patients and 19 liver-healthy controls. Blood was sampled from the hepatic vein and the femoral artery and suPAR was measured by enzyme-linked immunosorbent assay.ResultsWe identified significantly higher median suPAR concentrations among the cirrhotic patients (7.2 ng/ml in the hepatic vein; 6.8 ng/ml in the femoral artery) compared to the controls (2.6 ng/ml, respectively, p-values <0.001). However, the median hepatic suPAR formation was 0.0 ng/ml in both groups. We observed significantly increasing suPAR levels according to higher Child classes (4.5 ng/ml, 6.9 ng/ml and 9.0 ng/ml, Child A, B, C respectively; p-value<0.001), and significantly higher median suPAR concentrations in patients with ascites versus patients without ascites (8.1 ng/ml versus 5.3 ng/ml, respectively, p-value<0.001). suPAR levels were significantly related to bilirubin (r = 0.48, p<0.001), the hepatic venous pressure gradient (r = 0.39, p<0.001), the cardiac index (r = 0.24, p = 0.02) and the plasma volume (r = 0.33, p = 0.001), whereas suPAR levels were significantly inversely related to albumin (r = -0.59, p<0.001), plasma coagulation factors (r-0.39, p<0.001), the mean arterial pressure (r = -0.28, p = 0.004), the systemic vascular resistance (r = 0.26, p = 0.007), the indocyanine green clearance (r = -0.51, p<0,001) and the galactose elimination capacity (r = -0.39, p<0.001).ConclusionWe identified elevated suPAR concentration in cirrhotic patients, which correlated significantly with the degree of cirrhosis and liver failure, but we were not able to demonstrate hepatic suPAR generation per se. This suggests that further investigations of the source of suPAR in cirrhotic patients need to be undertaken.
| S-EPMC6715219 | biostudies-literature
Project description:Background Venous thromboembolism (VTE) contributes significantly to COVID-19 morbidity and mortality. The urokinase receptor system is involved in the regulation of coagulation. Levels of soluble urokinase plasminogen activator receptor (suPAR) reflect hyperinflammation and are strongly predictive of outcomes in COVID-19. Whether suPAR levels identify patients with COVID-19 at risk for VTE is unclear. Methods and Results We leveraged a multinational observational study of patients hospitalized for COVID-19 with suPAR and D-dimer levels measured on admission. In 1960 patients (mean age, 58 years; 57% men; 20% Black race), we assessed the association between suPAR and incident VTE (defined as pulmonary embolism or deep vein thrombosis) using logistic regression and Fine-Gray modeling, accounting for the competing risk of death. VTE occurred in 163 (8%) patients and was associated with higher suPAR and D-dimer levels. There was a positive association between suPAR and D-dimer (β=7.34; P=0.002). Adjusted for clinical covariables, including D-dimer, the odds of VTE were 168% higher comparing the third with first suPAR tertiles (adjusted odds ratio, 2.68 [95% CI, 1.51-4.75]; P<0.001). Findings were consistent when stratified by D-dimer levels and in survival analysis accounting for death as a competing risk. On the basis of predicted probabilities from random forest, a decision tree found the combined D-dimer <1 mg/L and suPAR <11 ng/mL cutoffs, identifying 41% of patients with only 3.6% VTE probability. Conclusions Higher suPAR was associated with incident VTE independently of D-dimer in patients hospitalized for COVID-19. Combining suPAR and D-dimer identified patients at low VTE risk. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04818866.
| S-EPMC9683642 | biostudies-literature
Project description:Background and objectivesBlack Americans with and without APOL1 kidney disease risk variants face high risk of ESKD. Soluble urokinase-type plasminogen activator receptor (suPAR), a circulating signaling protein and marker of immune activation, constitutes a promising biomarker of CKD-associated risks. We aimed to quantify the associations between serum suPAR concentration and adverse outcomes in Black Americans with and without APOL1 kidney disease risk variants, over and above iodine-125 iothalamate measured GFR and proteinuria.Design, setting, participants, & measurementsUsing data from the African-American Study of Kidney Disease and Hypertension, a multicenter clinical trial followed by a cohort phase with a median total follow-up of 9.7 years (interquartile range, 6.5-10.9 years), we examined the associations of suPAR with CKD progression (defined as doubling of serum creatinine or ESKD), ESKD, worsening proteinuria (defined as pre-ESKD doubling of 24-hour urine protein-to-creatinine ratio to ≥220 mg/g), and all-cause death.ResultsAt baseline, the median suPAR was 4462 pg/ml, mean measured GFR was 46 ml/min per 1.73 m2, and median 24-hour urine protein-to-creatinine ratio was 80 mg/g. After controlling for baseline demographics, randomization arm, GFR, proteinuria, APOL1 risk status, and clinical risk factors, there was a 1.26-times higher risk for CKD progression per SD higher baseline log-transformed suPAR (hazard ratio [HR], 1.26; 95% confidence interval [95% CI], 1.11 to 1.43; P<0.001). Higher suPAR was also independently associated with risk of ESKD (HR, 1.36; 95% CI, 1.17 to 1.58; P<0.001) and death (HR, 1.25; 95% CI, 1.08 to 1.45; P=0.003). suPAR was only associated with worsening proteinuria in patients with two APOLI risk alleles (HR, 1.46; 95% CI, 1.08 to 1.99; P=0.02).ConclusionsHigher suPAR was associated with various adverse outcomes in Black Americans with CKD, with and without APOL1 kidney disease risk variants, independently of proteinuria and GFR.
| S-EPMC6032570 | biostudies-literature
Project description:The soluble urokinase-type plasminogen activator receptor (suPAR) and the urokinase-type plasminogen activator receptor (uPAR) have been proposed as useful biomarkers of tumor progression. Recently, suPAR was associated with chemoresistance in lung cancer. However, its clinical significance in leukemia has not previously been investigated. The present study examined the plasma levels of suPAR and the expression of the uPAR on bone marrow (BM) cells in 86 patients with leukemia at diagnosis prior to chemotherapy and 26 normal subjects (control group). The plasma suPAR levels were measured using ELISA, whilst uPAR expression was assayed by flow cytometry analysis. In addition, cell surface uPAR expression on K562 and multidrug-resistant K562/ADM cell lines was studied by western blotting. On admission and follow-up, the levels of suPAR in patients with leukemia were significantly increased compared with controls. Systemic levels of suPAR were strongly associated with the numbers of white blood cells. A case was defined as uPAR-positive (uPAR+) if >20% of the gated cells expressed uPAR. In comparison with 26 healthy BM samples that were negative for uPAR expression, 48 (55.8%) of the 86 leukemia patients were uPAR+. uPAR expression on the cell surface of multidrug-resistant K562/ADM cells was increased compared with that on K562 cells. In conclusion, plasma suPAR expression may be a useful marker for subtype classification of patients with leukemia and cell surface uPAR may be associated with resistance to chemotherapy or disease progression.
| S-EPMC5494859 | biostudies-other
Project description:Data from clinical studies, cell culture, and animal models implicate the urokinase (uPA)/Plasminogen (Plg) system in the development of atherosclerosis and aneurysms. However, the mechanisms through which uPA/Plg stimulate these diseases are not yet defined. We used genetically modified, atherosclerosis-prone mice, including mice with macrophage-specific uPA overexpression to clarify mechanisms of uPA/Plg-accelerated atherosclerosis and aneurysm formation. Microarray studies were performed to identify potential mediators of uPA-accelerated atherosclerosis. These studies identified S100A8 and S100A9 mRNA as the most highly upregulated transcripts in uPA-overexpressing macrophages; upregulation of S100A9 protein in uPA-overexpressing macrophages was confirmed by Western blotting. S100A8/A9, which are atherogenic in mice and are expressed in human atherosclerotic plaques, are also upregulated in aortae of mice with uPA-overexpressing macrophages, and macrophage S100A9 mRNA is upregulated by exposure of wild-type macrophages to medium from uPA-overexpressing macrophages. Bioinformatics analysis of the microarray data suggest significant effects of uPA overexpression on cell migration and cell-matrix interactions. Our results confirm—in a second animal model—that macrophage-expressed uPA stimulates atherosclerosis and aortic dilation. They also implicate specific pathways in uPA/Plg-accelerated atherosclerosis and aneurysmal disease.
2011-05-03 | GSE29028 | GEO
Project description:BACKGROUND AND AIMS:Circulating soluble urokinase plasminogen activator receptor (suPAR) is a marker of immune activation associated with atherosclerosis. Whether suPAR levels are associated with prevalent peripheral arterial disease (PAD) and its adverse outcomes remains unknown and is the aim of the study. METHODS:SuPAR levels were measured in 5810 patients (mean age 63 years, 63% male, 77% with obstructive coronary artery disease [CAD]) undergoing cardiac catheterization. The presence of PAD (n = 967, 17%) was classified as carotid (36%), lower/upper extremities (30%), aortic (15%) and multisite disease (19%). Multivariable logistic and Cox regression models were used to determine independent predictors of prevalent PAD and outcomes including all-cause death, cardiovascular death and PAD-related events after adjustment for age, gender, race, body mass index, smoking, diabetes, hypertension, hyperlipidemia, renal function, heart failure history, and obstructive CAD. RESULTS:Plasma suPAR levels were 22.5% (p < 0.001) higher in patients with PAD compared to those without PAD. Plasma suPAR was higher in patients with more extensive PAD (?2 compared to single site) p < 0.001. After multivariable adjustment, suPAR was associated with prevalent PAD; odds ratio (OR) for highest compared to lowest tertile of 2.0, 95% CI (1.6-2.5) p < 0.001. In Cox survival analyses adjusted for clinical characteristics and medication regimen, suPAR (in the highest vs. lowest tertile) remained an independent predictor of all-cause death [HR 3.1, 95% CI (1.9-5.3)], cardiovascular death [HR 3.5, 95% CI (1.8-7.0)] and PAD-related events [HR = 1.8, 95% CI (1.3-2.6) p < 0.001 for all]. CONCLUSIONS:Plasma suPAR level is predictive of prevalent PAD and of incident cardiovascular and PAD-related events. Whether SuPAR measurement can help screen, risk stratify, or monitor therapeutic responses in PAD requires further investigation.
| S-EPMC5808930 | biostudies-literature