Domain 1 of the urokinase‐type plasminogen activator receptor is required for its morphologic and functional, β2 integrin–mediated connection with actin cytoskeleton in human microvascular endothelial cells: Failure of association in systemic sclerosis endothelial cells

Margheri, Francesca; Manetti, Mirko; Serratì, Simona; Nosi, Daniele; Pucci, Marco; Matucci‐Cerinic, Marco; Kahaleh, Bashar; Bazzichi, Laura; Fibbi, Gabriella; Ibba‐Manneschi, Lidia; Rosso, Mario Del

doi:10.1002/art.22263

Cited by 76 publications

(76 citation statements)

References 44 publications

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“…In contrast, our proteomics analysis identified ␤2 integrin, which is known to be abundantly expressed in endothelial progenitor cells (43) and also microvascular endothelial cells (44,45). For example, ␤2 integrin plays an important role in angiogenic properties of skin microvascular endothelial cells through its interaction with actin cytoskeleton (44). In addition to proteomic analyses of the whole retinal samples, we confirmed VEGF-induced expression of ␤2 integrin in retinal microvascular endothelial cells on FN1-coated dish.…”

Section: Molecular and Cellular Proteomics 155supporting

confidence: 49%

“…As the downstream factors of FN1, previous studies, most of which are based on experiments with endothelial cells from large vessels, have identified the integrins ␣v, ␣3, ␣5, ␤1, and ␤3 (41,42). In contrast, our proteomics analysis identified ␤2 integrin, which is known to be abundantly expressed in endothelial progenitor cells (43) and also microvascular endothelial cells (44,45). For example, ␤2 integrin plays an important role in angiogenic properties of skin microvascular endothelial cells through its interaction with actin cytoskeleton (44).…”

Section: Molecular and Cellular Proteomics 155mentioning

confidence: 61%

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Quantitative Proteomics Reveals β2 Integrin-mediated Cytoskeletal Rearrangement in Vascular Endothelial Growth Factor (VEGF)-induced Retinal Vascular Hyperpermeability

Bae

Chae

et al. 2016

Molecular & Cellular Proteomics

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Retinal vascular hyperpermeability causes macular edema, leading to visual deterioration in retinal diseases such as diabetic retinopathy and retinal vascular occlusion. Dysregulation of junction integrity between endothelial cells by vascular endothelial growth factor (VEGF) was shown to cause retinal vascular hyperpermeability. Accordingly, anti-VEGF agents have been used to treat retinal vascular hyperpermeability. However, they can confer potential toxicity through their deleterious effects on maintenance and survival of neuronal and endothelial cells in the retina. Thus, it is important to identify novel therapeutic targets for retinal vascular hyperpermeability other than VEGF. Here, we prepared murine retinas showing VEGF-induced vascular leakage from superficial retinal vascular plexus and prevention of VEGF-induced leakage by anti-VEGF antibody treatment. We then performed comprehensive proteome profiling of these samples and identified retinal proteins for which abundances were differentially expressed by VEGF, but such alterations were inhibited by anti-VEGF antibody. Functional enrichment and network analyses of these proteins revealed the ␤2 integrin pathway, which can prevent dysregulation of junction integrity between endothelial cells through cytoskeletal rearrangement, as a potential therapeutic target for retinal vascular hyperpermeability. Finally, we experimentally demonstrated that inhibition of the ␤2 integrin pathway salvaged VEGF-induced retinal vascular hyperpermeability, supporting its validity as an alternative therapeutic target to anti-VEGF agents. Molecular & Cellular Proteomics

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Section: Molecular and Cellular Proteomics 155supporting

confidence: 49%

Section: Molecular and Cellular Proteomics 155mentioning

confidence: 61%

Quantitative Proteomics Reveals β2 Integrin-mediated Cytoskeletal Rearrangement in Vascular Endothelial Growth Factor (VEGF)-induced Retinal Vascular Hyperpermeability

Bae

Chae

et al. 2016

Molecular & Cellular Proteomics

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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).…”

Section: Functional Overviewmentioning

confidence: 99%

“…The crystal structure of uPAR in complex with a peptide antagonist was solved in 2005 (33). The subsequent identification of additional extracellular ligands and cell surface co-receptor suggests its possible roles independent of the enzymatic properties of its ligand urokinase (26,34,35). The currently known ligands are uPA ± PAI-1, vitronectin, and kininogen (23,34,36).…”

Section: Functional Overviewmentioning

confidence: 99%

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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“…Since then, uPAR and suPAR have been investigated both in humans and in animal models of OA [77][78][79][80][81], RA [26,77,78,80,[82][83][84][85][86][87][88], gouty arthritis [89], and ankylosing spondylitis [90]. There are also observations on involvement of the uPAR system in systemic sclerosis [91][92][93] and Behçet's disease [94]. The first report on suPAR in SLE was presented by us as an abstract at the 2011 meeting of the American Colleague of Rheumatology [1,14].…”

Section: Supar As a Biomarker In Sle And Other Rheumatic Diseasesmentioning

confidence: 99%

Soluble urokinase plasminogen activator receptor—A valuable biomarker in systemic lupus erythematosus?

Enocsson¹,

Sjöwall²,

Wetterö³

2015

Clinica Chimica Acta

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The expression of uPAR is mainly regulated by growth factors and pro-inflammatory cytokines like basic fibroblast growth factor, epidermal growth factor, tumor necrosis factor, interleukin ( suPAR as a clinical marker of inflammation and organ damagePlasma membrane expression of uPAR as well as the levels of circulating suPAR have been investigated in relation to a broad range of conditions and suPAR has been referred to as a "molecular crystal ball" due to its prognostic value in diseases like tuberculosis, HIV, sepsis and cancer [2,6,13,26,58,59]. Further, it has been reported that it reflects overall immune activation and systemic inflammation [2]. suPAR has also emerged as a potential biomarker of fibrosis in chronic liver diseases of diverse etiology [10,11,[60][61][62].Recently, suPAR attracted significant attention in primary focal segmental glomerulosclerosis (FSGS). data from this pilot study revealed significantly higher suPAR levels among patients with moderately or highly elevated SDI after study inclusion, compared to patients without SDI increase (Figure 2).Furthermore, there were higher death rates among patients in the two groups with SDI increase (Figure 2). However, it is well known that present organ damage predicts further organ damage [17,100], and thus, adjustment for SDI at baseline should be performed to reduce the risk of bias. A stepwise linear multiple regression analysis was therefore performed to evaluate the impact of suPAR on future SDI increase. After adjusting for age, sex and SDI at study inclusion, we found suPAR levels to have a significant impact on future SDI increase (p = 0.005, standardized β = 0.20) whereas SDI at study inclusion was excluded from the model. Since recent studies have revealed an inverse correlation between serum suPAR and glomerular filtration [67,68,96], we also included estimated glomerular filtration (eGFR) (calculated by the 4-variable Modification of Diet in Renal Disease StudyGroup formula [101]) in the analysis, but eGFR was not retained in the model. From these results, we suggest that suPAR can actually predict organ damage independent of present SDI score or eGFR, but that a prospective study examining the association between suPAR levels at the time of diagnosis with future SDI would be preferable.In line with these findings, elevated suPAR levels have previously been demonstrated to associate with the risk of developing cancer, cardiovascular disease and type 2 diabetes later in life in the general population [7]. Importantly, these associations were independent of CRP, which is known for its predictive value in cardiovascular disease [7,102].7 Potential roles of suPAR in SLE pathogenesisAssessment of circulating suPAR levels at the clinical laboratory could possibly become a future way to estimate organ damage in SLE, and suPAR would be an even more appealing biomarker candidate if the levels could be mechanistically linked to the disease. The pathogenesis of SLE is notoriously complex and not fully understood, but includes disturbances in t...

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Domain 1 of the urokinase‐type plasminogen activator receptor is required for its morphologic and functional, β2 integrin–mediated connection with actin cytoskeleton in human microvascular endothelial cells: Failure of association in systemic sclerosis endothelial cells

Cited by 76 publications

References 44 publications

Quantitative Proteomics Reveals β2 Integrin-mediated Cytoskeletal Rearrangement in Vascular Endothelial Growth Factor (VEGF)-induced Retinal Vascular Hyperpermeability

Quantitative Proteomics Reveals β2 Integrin-mediated Cytoskeletal Rearrangement in Vascular Endothelial Growth Factor (VEGF)-induced Retinal Vascular Hyperpermeability

Urokinase and its receptors in chronic kidney disease

Soluble urokinase plasminogen activator receptor—A valuable biomarker in systemic lupus erythematosus?

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