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1.
Nat Commun ; 15(1): 7963, 2024 Sep 11.
Artículo en Inglés | MEDLINE | ID: mdl-39261453

RESUMEN

Coagulation factor XII (FXII) conveys various functions as an active protease that promotes thrombosis and inflammation, and as a zymogen via surface receptors like urokinase-type plasminogen activator receptor (uPAR). While plasma levels of FXII are increased in diabetes mellitus and diabetic kidney disease (DKD), a pathogenic role of FXII in DKD remains unknown. Here we show that FXII is locally expressed in kidney tubular cells and that urinary FXII correlates with kidney dysfunction in DKD patients. F12-deficient mice (F12-/-) are protected from hyperglycemia-induced kidney injury. Mechanistically, FXII interacts with uPAR on tubular cells promoting integrin ß1-dependent signaling. This signaling axis induces oxidative stress, persistent DNA damage and senescence. Blocking uPAR or integrin ß1 ameliorates FXII-induced tubular cell injury. Our findings demonstrate that FXII-uPAR-integrin ß1 signaling on tubular cells drives senescence. These findings imply previously undescribed diagnostic and therapeutic approaches to detect or treat DKD and possibly other senescence-associated diseases.


Asunto(s)
Senescencia Celular , Nefropatías Diabéticas , Factor XII , Integrina beta1 , Receptores del Activador de Plasminógeno Tipo Uroquinasa , Animales , Femenino , Humanos , Masculino , Ratones , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Nefropatías Diabéticas/genética , Factor XII/metabolismo , Factor XII/genética , Integrina beta1/metabolismo , Integrina beta1/genética , Túbulos Renales/metabolismo , Túbulos Renales/patología , Ratones Endogámicos C57BL , Ratones Noqueados , Estrés Oxidativo , Receptores del Activador de Plasminógeno Tipo Uroquinasa/metabolismo , Receptores del Activador de Plasminógeno Tipo Uroquinasa/genética , Transducción de Señal
2.
Front Immunol ; 15: 1410948, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38975344

RESUMEN

Background: Chronic rhinosinusitis (CRS) is an inflammatory disease affecting more than 10% of the global adult population. It is classified into Th1, Th2, and Th17 endotypes and eosinophilic and non-eosinophilic types. Th2-based inflammation and eosinophilic CRS (ECRS) are associated with tissue remodeling and fibrinolytic system impairment. Objective: To elucidate the role of eosinophils in inducing fibrin deposition in CRS nasal polyp tissues and explore potential regulatory mechanisms. Methods: We analyzed the expression of genes related to the serpin family and fibrinolytic system using Gene Expression Omnibus and Next-generation sequencing data. Differentially expression genes (DEGs) analysis was used to compare control and nasal polyp tissues, followed by KEGG and Gene ontology (GO) analysis. We measured the expression and correlation of plasminogen activator-1 (PAI-1), tissue plasminogen activator (t-PA), urokinase plasminogen activator (u-PA), and urokinase plasminogen activator surface receptor (u-PAR) in CRS tissues, and evaluated the effect of eosinophils on the fibrinolytic system using a cytokine array and co-culture. Results: Nasal polyp tissues showed upregulated PAI-1, u-PA, and u-PAR expression and downregulated t-PA expression. Fibrinolytic system-related genes positively correlated with Th2 cytokines, except for t-PA. Eosinophil-derived Chitinase-3-like protein 1 (CHI3L1) increased PAI-1 expression and decreased t-PA levels in fibroblasts and epithelial cells. The inhibition of CHI3L1 suppresses these alterations. Conclusion: CHI3L1 contributes to fibrin deposition by impairing the fibrinolytic system during nasal polyp formation. The regulation of CHI3L1 expression may inhibit fibrin deposition and edema in ECRS, presenting a potential treatment for this condition.


Asunto(s)
Proteína 1 Similar a Quitinasa-3 , Eosinófilos , Fibrinólisis , Pólipos Nasales , Inhibidor 1 de Activador Plasminogénico , Rinitis , Sinusitis , Humanos , Pólipos Nasales/metabolismo , Pólipos Nasales/inmunología , Sinusitis/metabolismo , Sinusitis/inmunología , Rinitis/metabolismo , Rinitis/inmunología , Enfermedad Crónica , Inhibidor 1 de Activador Plasminogénico/metabolismo , Inhibidor 1 de Activador Plasminogénico/genética , Proteína 1 Similar a Quitinasa-3/metabolismo , Proteína 1 Similar a Quitinasa-3/genética , Adulto , Femenino , Masculino , Persona de Mediana Edad , Eosinófilos/inmunología , Eosinófilos/metabolismo , Receptores del Activador de Plasminógeno Tipo Uroquinasa/genética , Receptores del Activador de Plasminógeno Tipo Uroquinasa/metabolismo , Activador de Plasminógeno de Tipo Uroquinasa/genética , Activador de Plasminógeno de Tipo Uroquinasa/metabolismo , Activador de Tejido Plasminógeno/metabolismo , Activador de Tejido Plasminógeno/genética , Citocinas/metabolismo , Rinosinusitis
3.
Oncol Rep ; 52(2)2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38940353

RESUMEN

The prognosis of patients with human papillomavirus (HPV)­negative cervical cancer is significantly worse than that of patients with HPV­positive cervical cancer. Understanding the mechanisms of this is crucial for preventing disease evolution. In the present study, the GV367­snail family transcriptional repressor 2 (SNAI2) lentiviral vector was constructed and transduced into C­33A cells. Subsequently, the proliferation of tumor cells was detected using the Cell Counting Kit (CCK)­8 method. Flow cytometry was used to analyze the cell cycle progression of tumor cells. The glucose consumption of tumor cells was detected using an oxidase assay, and the senescence of tumor cells was detected using beta­galactosidase staining. The gene expression and the activity of p38 and ERK1/2 were detected using reverse transcription­quantitative PCR and western blotting, respectively. The C­33A­SNAI2 cell line was successfully established. Compared with HeLa and C­33A­Wild cells, the proliferation and percentage of G0/G1­phase cells in the C­33A­SNAI2 group were decreased, as detected by the CCK­8 assay (100±0 vs. 239.1±58.3 vs. 39.7±20.1, P<0.01) and flow cytometry (34.0±7.1% vs. 46.2±10.6% vs. 61.3±5.3%, P<0.05). Compared with the HeLa group, the glucose consumption of the C­33A­Wild and C­33A­SNAI2 groups was significantly decreased (P<0.01). The results of beta­galactosidase staining showed that the proportion of beta­galactosidase­positive cells in the C­33A­SNAI2 group was significantly decreased compared with the C­33A­Wild group (P<0.01). Upregulation of SNAI2 enhanced the increase in p21 expression, and the decrease in CDK1, urokinase plasminogen activator receptor (u­PAR) and cyclin D1 expression in C­33A cells compared with C­33A­Wild cells (P<0.05). In addition, the activities of p38, ERK1/2 and the phosphorylated (p)­ERK1/2/p­p38 ratio were decreased in the C­33A­SNAI2 group compared with the C­33A­Wild and HeLa groups (P<0.05). In conclusion, SNAI2 enhanced HPV­negative cervical cancer C­33A cell dormancy, which was characterized by G0/G1 arrest, by the downregulation of u­PAR expression, and a decrease in the activity of the p­ERK1/2 and p­p38MAPK signaling pathways in vitro. Cancer recurrence and metastases are responsible for most cancer­related deaths. Given that SNAI2 is required for enhancing HPV­negative cervical cancer cell dormancy, regulating this process may promote cervical tumor cells to enter a continuous dormant state, which could be a potential approach for tumor therapy.


Asunto(s)
Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Factores de Transcripción de la Familia Snail , Neoplasias del Cuello Uterino , Humanos , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/virología , Neoplasias del Cuello Uterino/metabolismo , Femenino , Factores de Transcripción de la Familia Snail/metabolismo , Factores de Transcripción de la Familia Snail/genética , Sistema de Señalización de MAP Quinasas , Células HeLa , Receptores del Activador de Plasminógeno Tipo Uroquinasa/genética , Receptores del Activador de Plasminógeno Tipo Uroquinasa/metabolismo , Línea Celular Tumoral , Papillomaviridae/genética , Senescencia Celular , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Ciclo Celular
4.
Curr Pharm Des ; 30(21): 1630-1640, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38715331

RESUMEN

The expression of human PLAUR gene, which encodes the urokinase plasminogen activator receptor (uPAR), is cell- and process-specific and elevated in inflammation, cancer and senescence. Its tight regulation is achieved by regulatory elements in the gene locus, such as the promoter and several enhancers. The promoter activity is not specific to a particular cell type and has been described earlier. The proximal enhancer is endothelial-specific and responsible for the PLAUR expression pattern in endothelial cells. In this study we described the enhancer activity and its cis-regulatory elements based on the published data. We showed a possible connection of the enhancer activity with known cellular phenotypes.


Asunto(s)
Elementos de Facilitación Genéticos , Interleucina-1beta , Receptores del Activador de Plasminógeno Tipo Uroquinasa , Factor de Necrosis Tumoral alfa , Factor A de Crecimiento Endotelial Vascular , Humanos , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/genética , Elementos de Facilitación Genéticos/genética , Receptores del Activador de Plasminógeno Tipo Uroquinasa/metabolismo , Receptores del Activador de Plasminógeno Tipo Uroquinasa/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Interleucina-1beta/metabolismo , Interleucina-1beta/genética , Células Endoteliales/metabolismo , Células Endoteliales/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Animales
5.
J Alzheimers Dis ; 99(1): 241-250, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38669542

RESUMEN

Background: The role of the innate immune system has long been associated with Alzheimer's disease (AD). There is now accumulating evidence that the soluble Urokinase Plasminogen Activator Receptor pathway, and its genes, PLAU and PLAUR may be important in AD, and yet there have been few genetic association studies to explore this. Objective: This study utilizes the DNA bank of the Brains for Dementia Research cohort to investigate the genetic association of common polymorphisms across the PLAU and PLAUR genes with AD. Methods: TaqMan genotyping assays were used with standard procedures followed by association analysis in PLINK. Results: No association was observed between the PLAU gene and AD; however, two SNPs located in the PLAUR gene were indicative of a trend towards association but did not surpass multiple testing significance thresholds. Conclusions: Further genotyping studies and exploration of the consequences of these SNPs on gene expression and alternative splicing are warranted to fully uncover the role this system may have in AD.


Asunto(s)
Enfermedad de Alzheimer , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Receptores del Activador de Plasminógeno Tipo Uroquinasa , Activador de Plasminógeno de Tipo Uroquinasa , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Enfermedad de Alzheimer/genética , Estudios de Cohortes , Predisposición Genética a la Enfermedad/genética , Genotipo , Polimorfismo de Nucleótido Simple/genética , Receptores del Activador de Plasminógeno Tipo Uroquinasa/genética , Activador de Plasminógeno de Tipo Uroquinasa/genética
6.
J Hepatol ; 81(2): 207-217, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38508241

RESUMEN

BACKGROUND & AIMS: Hepatic stellate cells (HSCs) are the key drivers of fibrosis in metabolic dysfunction-associated steatohepatitis (MASH), the fastest growing cause of hepatocellular carcinoma (HCC) worldwide. HSCs are heterogenous, and a senescent subset of HSCs is implicated in hepatic fibrosis and HCC. Administration of anti-uPAR (urokinase-type plasminogen activator receptor) CAR T cells has been shown to deplete senescent HSCs and attenuate fibrosis in murine models. However, the comprehensive features of senescent HSCs in MASH, as well as their cellular ontogeny have not been characterized; hence, we aimed to comprehensively characterize and define the origin of HSCs in human and murine MASH. METHODS: To comprehensively characterize the phenotype and ontogeny of senescent HSCs in human and murine MASH, we integrated senescence-associated beta galactosidase activity with immunostaining, flow cytometry and single-nucleus RNA sequencing (snRNAseq). We integrated the immunohistochemical profile with a senescence score applied to snRNAseq data to characterize senescent HSCs and mapped the evolution of uPAR expression in MASH. RESULTS: Using pseudotime trajectory analysis, we establish that senescent HSCs arise from activated HSCs. While uPAR is expressed in MASH, the magnitude and cell-specificity of its expression evolve with disease stage. In early disease, uPAR is more specific to activated and senescent HSCs, while it is also expressed by myeloid-lineage cells, including Trem2+ macrophages and myeloid-derived suppressor cells, in late disease. Furthermore, we identify novel surface proteins expressed on senescent HSCs in human and murine MASH that could be exploited as therapeutic targets. CONCLUSIONS: These data define features of HSC senescence in human and murine MASH, establishing an important blueprint to target these cells as part of future antifibrotic therapies. IMPACT AND IMPLICATIONS: Hepatic stellate cells (HSCs) are the primary drivers of scarring in chronic liver diseases. As injury develops, a subset of HSCs become senescent; these cells are non-proliferative and pro-inflammatory, thereby contributing to worsening liver injury. Here we show that senescent HSCs are expanded in MASH (metabolic dysfunction-associated steatohepatitis) in humans and mice, and we trace their cellular origin from the activated HSC subset. We further characterize expression of uPAR (urokinase plasminogen activated receptor), a protein that marks senescent HSCs, and report that uPAR is also expressed by activated HSCs in early injury, and in immune cells as liver injury advances. We have integrated high-resolution single-nucleus RNA sequencing with immunostaining and flow cytometry to identify five other novel proteins expressed by senescent HSCs, including mannose receptor CD206, which will facilitate future therapeutic development.


Asunto(s)
Senescencia Celular , Células Estrelladas Hepáticas , Fenotipo , Células Estrelladas Hepáticas/metabolismo , Senescencia Celular/fisiología , Animales , Humanos , Ratones , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Hígado Graso/metabolismo , Hígado Graso/etiología , Hígado Graso/patología , Receptores del Activador de Plasminógeno Tipo Uroquinasa/metabolismo , Receptores del Activador de Plasminógeno Tipo Uroquinasa/genética , Modelos Animales de Enfermedad , Masculino , Ratones Endogámicos C57BL
7.
Int J Mol Sci ; 25(4)2024 Feb 07.
Artículo en Inglés | MEDLINE | ID: mdl-38396677

RESUMEN

Urokinase plasminogen activator receptor (uPAR) encoded by the PLAUR gene is known as a clinical marker for cell invasiveness in glioblastoma multiforme (GBM). It is additionally implicated in various processes, including angiogenesis and inflammation within the tumor microenvironment. However, there has not been a comprehensive study that depicts the overall functions and molecular cooperators of PLAUR with respect to intra-tumoral subtypes of GBM. Using single-cell RNA sequencing data from 37 GBM patients, we identified PLAUR as a marker gene for two distinct subtypes in GBM. One subtype is featured by inflammatory activities and the other subtype is marked by ECM remodeling processes. Using the whole-transcriptome data from single cells, we are able to uncover the molecular cooperators of PLAUR for both subtypes without presuming biological pathways. Two protein networks comprise the molecular context of PLAUR, with each of the two subtypes characterized by a different dominant network. We concluded that targeting PLAUR directly influences the mechanisms represented by these two protein networks, regardless of the subtype of the targeted cell.


Asunto(s)
Glioblastoma , Receptores del Activador de Plasminógeno Tipo Uroquinasa , Humanos , Glioblastoma/metabolismo , Receptores del Activador de Plasminógeno Tipo Uroquinasa/genética , Receptores del Activador de Plasminógeno Tipo Uroquinasa/metabolismo , Análisis de Secuencia de ARN , Transducción de Señal , Microambiente Tumoral/genética , Análisis de Expresión Génica de una Sola Célula , Biomarcadores de Tumor
8.
Cancer Biomark ; 39(2): 137-153, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38073374

RESUMEN

BACKGROUND: Despite advances in lung cancer treatment, most lung cancers are diagnosed at an advanced stage. Expression of microRNA10b (miR-10b) and fibrinolytic activity, as reflected by soluble urokinase-type plasminogen activator receptor (suPAR) and plasminogen activator inhibitor 1 (PAI-1), are promising biomarker candidates. OBJECTIVE: To assess the expression of miR-10b, and serum levels of suPAR and PAI-1 in advanced stage non-small cell lung cancer (NSCLC) patients, and their correlation with progression, treatment response and prognosis. METHODS: The present prospective cohort and survival study was conducted at Dharmais National Cancer Hospital and included advanced stage NSCLC patients diagnosed between March 2015 and September 2016. Expression of miR-10b was quantified using qRT-PCR. Levels of suPAR and PAI-1 were assayed using ELISA. Treatment response was evaluated using the RECIST 1.1 criteria. Patients were followed up until death or at least 1 year after treatment. RESULTS: Among the 40 patients enrolled, 25 completed at least four cycles of chemotherapy and 15 patients died during treatment. Absolute miR-10b expression ⩾ 592,145 copies/µL or miR-10b fold change ⩾ 0.066 were protective for progressive disease and poor treatment response, whereas suPAR levels ⩾ 4,237 pg/mL was a risk factor for progressive disease and poor response. PAI-1 levels > 4.6 ng/mL was a protective factor for poor response. Multivariate analysis revealed suPAR as an independent risk factor for progression (ORa⁢d⁢j, 13.265; 95% confidence intervals (CI), 2.26577.701; P= 0.006) and poor response (ORa⁢d⁢j, 15.609; 95% CI, 2.221-109.704; P= 0.006), whereas PAI-1 was an independent protective factor of poor response (ORa⁢d⁢j, 0.127; 95% CI, 0.019-0.843; P= 0.033). CONCLUSIONS: Since miR-10b cannot be used as an independent risk factor for NSCLC progression and treatment response, we developed a model to predict progression using suPAR levels and treatment response using suPAR and PAI-1 levels. Further studies are needed to validate this model.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , MicroARNs , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , MicroARNs/genética , Inhibidor 1 de Activador Plasminogénico/genética , Estudios Prospectivos , Receptores del Activador de Plasminógeno Tipo Uroquinasa/genética
9.
Int J Mol Sci ; 24(21)2023 Oct 25.
Artículo en Inglés | MEDLINE | ID: mdl-37958542

RESUMEN

One of the largest challenges to the implementation of cardiac cell therapy is identifying selective reparative targets to enhance stem/progenitor cell therapeutic efficacy. In this work, we hypothesized that such a target could be an urokinase-type plasminogen activator receptor (uPAR)-a glycosyl-phosphatidyl-inositol-anchored membrane protein, interacting with urokinase. uPAR is able to form complexes with various transmembrane proteins such as integrins, activating intracellular signaling pathway and thus regulating multiple cell functions. We focused on studying the CD117+ population of cardiac mesenchymal progenitor cells (MPCs), expressing uPAR on their surface. It was found that the number of CD117+ MPCs in the heart of the uPAR-/- mice is lower, as well as their ability to proliferate in vitro compared with cells from wild-type animals. Knockdown of uPAR in CD117+ MPCs of wild-type animals was accompanied by a decrease in survival rate and Akt signaling pathway activity and by an increase in the level of caspase activity in these cells. That suggests the role of uPAR in supporting cell survival. After intramyocardial transplantation of uPAR(-) MPCs, reduced cell retention and angiogenesis stimulation were observed in mice with myocardial infarction model compared to uPAR(+) cells transplantation. Taken together, the present results appear to prove a novel mechanism of uPAR action in maintaining the survival and angiogenic properties of CD117+ MPCs. These results emphasize the importance of the uPAR as a potential pharmacological target for the regulation of reparative properties of myocardial mesenchymal progenitor cells.


Asunto(s)
Células Madre Mesenquimatosas , Miocardio , Receptores del Activador de Plasminógeno Tipo Uroquinasa , Animales , Ratones , Integrinas , Células Madre Mesenquimatosas/metabolismo , Receptores del Activador de Plasminógeno Tipo Uroquinasa/genética , Receptores del Activador de Plasminógeno Tipo Uroquinasa/metabolismo , Transducción de Señal , Activador de Plasminógeno de Tipo Uroquinasa/genética , Activador de Plasminógeno de Tipo Uroquinasa/metabolismo , Miocardio/citología
10.
Funct Integr Genomics ; 23(3): 269, 2023 Aug 08.
Artículo en Inglés | MEDLINE | ID: mdl-37552345

RESUMEN

It is well-established that breast cancer is a highly prevalent malignancy among women, emphasizing the need to investigate mechanisms underlying its pathogenesis and metastasis. In this study, the Gene Expression Omnibus (GEO) database was utilized to conduct differential expression analysis in breast cancer and adjacent tissues. Upregulated genes were selected for prognostic analysis of breast cancer. The expression of urokinase plasminogen activator receptor (uPAR), also known as PLAUR, was assessed using RT-qPCR and western blot. Immunofluorescence staining was employed to determine PLAUR localization. Various cellular processes were analyzed, including proliferation, migration, invasion, apoptosis, and cell cycle. Bioinformatics analysis was used to predict transcription factors of PLAUR, which were subsequently validated in a double luciferase reporter gene experiment. Rescue experiments confirmed the impact of PLAUR on the proliferation, apoptosis, and migration of MDA-MB-231 cells. Furthermore, the effects of PLAUR were evaluated in an orthotopic tumor transplantation and lung metastasis nude mouse model. Our findings substantiated the critical involvement of PLAUR in the progression of triple-negative breast cancer (TNBC) in vitro and among TNBC patients with a poor prognosis. Additionally, we demonstrated Yin Yang-1 (YY1) as a notable transcriptional regulator of PLAUR, whose activation could transcriptionally enhance the proliferation and invasion capabilities of TNBC cells. We also identified the downstream mechanism of PLAUR associated with PLAU, focal adhesion kinase (FAK), and AKT. Overall, these findings offer a novel perspective on PLAUR as a potential therapeutic target for TNBC.


Asunto(s)
Neoplasias Pulmonares , Receptores del Activador de Plasminógeno Tipo Uroquinasa , Neoplasias de la Mama Triple Negativas , Factor de Transcripción YY1 , Animales , Femenino , Humanos , Ratones , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/genética , Transducción de Señal , Neoplasias de la Mama Triple Negativas/genética , Factor de Transcripción YY1/genética , Factor de Transcripción YY1/metabolismo , Receptores del Activador de Plasminógeno Tipo Uroquinasa/genética , Receptores del Activador de Plasminógeno Tipo Uroquinasa/metabolismo
11.
Nat Commun ; 14(1): 4414, 2023 07 21.
Artículo en Inglés | MEDLINE | ID: mdl-37479685

RESUMEN

Elevation in soluble urokinase receptor (suPAR) and proteinuria are common signs in patients with moderate to severe coronavirus disease 2019 (COVID-19). Here we characterize a new type of proteinuria originating as part of a viral response. Inoculation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes increased suPAR levels and glomerulopathy in African green monkeys. Using an engineered mouse model with high suPAR expression, inhaled variants of SARS-CoV-2 spike S1 protein elicite proteinuria that could be blocked by either suPAR antibody or SARS-CoV-2 vaccination. In a cohort of 1991 COVID-19 patients, suPAR levels exhibit a stepwise association with proteinuria in non-Omicron, but not in Omicron infections, supporting our findings of biophysical and functional differences between variants of SARS-CoV-2 spike S1 protein and their binding to podocyte integrins. These insights are not limited to SARS-CoV-2 and define viral response proteinuria (VRP) as an innate immune mechanism and co-activation of podocyte integrins.


Asunto(s)
COVID-19 , Podocitos , Animales , Ratones , Chlorocebus aethiops , Humanos , Vacunas contra la COVID-19 , Receptores del Activador de Plasminógeno Tipo Uroquinasa/genética , SARS-CoV-2 , Integrinas , Proteinuria
12.
Sci Rep ; 13(1): 8533, 2023 05 26.
Artículo en Inglés | MEDLINE | ID: mdl-37237021

RESUMEN

Atherosclerosis (AS) is a major contributor to a variety of negative clinical outcomes, including stroke and myocardial infarction. However, the role and therapeutic value of hypoxia-related genes in AS development has been less discussed. In this study, Plasminogen activator, urokinase receptor (PLAUR) was identified as an effective diagnostic marker for AS lesion progression by combining WGCNA and random forest algorithm. We validated the stability of the diagnostic value on multiple external datasets including humans and mice. We identified a significant correlation between PLAUR expression and lesion progression. We mined multiple single cell-RNA sequencing (sc-RNA seq) data to nominate macrophage as the key cell cluster for PLAUR mediated lesion progression. We combined cross-validation results from multiple databases to predict that HCG17-hsa-miR-424-5p-HIF1A, a competitive endogenous RNA (ceRNA) network, may regulate hypoxia inducible factor 1 subunit alpha (HIF1A) expression. The DrugMatrix database was used to predict alprazolam, valsartan, biotin A, lignocaine, and curcumin as potential drugs to delay lesion progression by antagonizing PLAUR, and AutoDock was used to verify the binding ability of drugs and PLAUR. Overall, this study provides the first systematic identification of the diagnostic and therapeutic value of PLAUR in AS and offers multiple treatment options with potential applications.


Asunto(s)
Aterosclerosis , Receptores del Activador de Plasminógeno Tipo Uroquinasa , Humanos , Ratones , Animales , Receptores del Activador de Plasminógeno Tipo Uroquinasa/genética , Activadores Plasminogénicos , Activador de Plasminógeno de Tipo Uroquinasa , Hipoxia/genética , Aterosclerosis/diagnóstico , Aterosclerosis/genética
13.
JCI Insight ; 8(7)2023 04 10.
Artículo en Inglés | MEDLINE | ID: mdl-37036003

RESUMEN

Acute kidney injury (AKI) secondary to sepsis results in poor outcomes and conventional kidney function indicators lack diagnostic value. Soluble urokinase plasminogen activator receptor (suPAR) is an innate immune-derived molecule implicated in inflammatory organ damage. We characterized the diagnostic ability of longitudinal serum suPAR levels to discriminate severity and course of sepsis-induced AKI (SI-AKI) in 200 critically ill patients meeting Sepsis-3 criteria. The pathophysiologic relevance of varying suPAR levels in SI-AKI was explored in a polymicrobial sepsis model in WT, (s)uPAR-knockout, and transgenic suPAR-overexpressing mice. At all time points studied, suPAR provided a robust classification of SI-AKI disease severity, with improved prediction of renal replacement therapy (RRT) and mortality compared with established kidney biomarkers. Patients with suPAR levels of greater than 12.7 ng/mL were at highest risk for RRT or death, with an adjusted odds ratio of 7.48 (95% CI, 3.00-18.63). suPAR deficiency protected mice against SI-AKI. suPAR-overexpressing mice exhibited greater kidney damage and poorer survival through inflamed kidneys, accompanied by local upregulation of potent chemoattractants and pronounced kidney T cell infiltration. Hence, suPAR allows for an innate immune-derived and kidney function-independent staging of SI-AKI and offers improved longitudinal risk stratification. suPAR promotes T cell-based kidney inflammation, while suPAR deficiency improves SI-AKI.


Asunto(s)
Lesión Renal Aguda , Sepsis , Ratones , Animales , Receptores del Activador de Plasminógeno Tipo Uroquinasa/genética , Sepsis/complicaciones , Inflamación , Biomarcadores , Lesión Renal Aguda/diagnóstico , Ratones Transgénicos
14.
Proc Natl Acad Sci U S A ; 120(3): e2212991120, 2023 01 17.
Artículo en Inglés | MEDLINE | ID: mdl-36638209

RESUMEN

The urokinase-type plasminogen activator (uPA) system consists of the proteinase uPA, its receptor (PLAUR/uPAR). Under physiological conditions, uPA and PLAUR are predominantly expressed by blood cells, including neutrophils, monocytes, and macrophages, and play important roles in cell activation, adhesion, migration, and extravasation. Here, we report that PLAUR, which is highly expressed in macrophages and dendritic cells (DCs) but hardly expressed in CD4+ T cells, inhibits the release of HIV-1 progeny virions from the cell membrane. Silencing PLAUR markedly enhanced the transmission of HIV-1 in macrophages and DCs. We further demonstrated that PLAUR is localized at the cell membrane to block the release of HIV-1 virions. Interestingly, we found that uPA compromises the PLAUR-mediated inhibition to slightly enhance HIV-1 production in primary macrophages and DCs. In the absence of PLAUR, this enhanced effect induced by uPA is abrogated. In conclusion, PLAUR is a new anti-HIV-1 protein produced in both macrophages and DCs where it inhibits HIV-1 transmission. This discovery may provide a novel therapeutic target for combating HIV.


Asunto(s)
VIH-1 , Receptores del Activador de Plasminógeno Tipo Uroquinasa , Replicación Viral , Humanos , Membrana Celular/metabolismo , VIH-1/fisiología , Receptores del Activador de Plasminógeno Tipo Uroquinasa/genética , Receptores del Activador de Plasminógeno Tipo Uroquinasa/metabolismo , Activador de Plasminógeno de Tipo Uroquinasa/genética , Activador de Plasminógeno de Tipo Uroquinasa/metabolismo , Virión/metabolismo
15.
Biomol Biomed ; 23(2): 287-297, 2023 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-36124441

RESUMEN

Alteration of urokinase plasminogen activator receptor (uPAR) in neoplasms is a prerequisite for invasiveness and metastatic ability. In the present study, we aimed to evaluate the relationship of pre-chemotherapy soluble uPAR (suPAR) with the odds for metastasis, lack of disease control, and its predictive ability for progression-free survival (PFS). Baseline plasma suPAR levels were measured by ELISA in 89 patients with various cancers prior to initiation of systemic treatment. Patients were followed prospectively until metastatic progression or death. TCGA Pan-Cancer dataset was mined for available RNAseq expression data of the PLAUR gene in patients with breast, colon, and lung cancer, and therelevant genomic and clinical data were extracted for further analysis. Pre-chemotherapy suPAR levels were significantly associated with white blood cell counts and fibrinogen and were significantly elevated both in patients with metastatic disease and in patients with progression. Increasing suPAR was significantly associated with odds for progression in the prespecified multivariate analysis (odds ratio 2.47, 95% confidence interval 1.3 - 5.11). In univariate Cox regression, suPAR was predictive of shortened progression-free survival (PFS) (hazard ratio 1.065, 95% confidence interval 1.002 - 1.13; p = 0.041). There was a trend towards shortened PFS in patients with higher baseline suPAR levels (cutoff 8.1 ng/mL). In the TCGA lung cancer cohort, PLAUR mRNA expression was significantly associated with shortened PFS in both univariate and multivariate analyses. High PLAUR gene expression conferred significant survival disadvantage only in patients with colon and lung cancer. SuPAR may bear predictive potential for adverse outcomes in cancer, but its utility as a biomarker seems to be more pronounced in cancers with associated inflammatory state.


Asunto(s)
Neoplasias Pulmonares , Receptores del Activador de Plasminógeno Tipo Uroquinasa , Humanos , Biomarcadores , Neoplasias Pulmonares/tratamiento farmacológico , Análisis Multivariante , Modelos de Riesgos Proporcionales , Receptores del Activador de Plasminógeno Tipo Uroquinasa/genética
16.
Curr Pharm Des ; 29(2): 149-161, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36515042

RESUMEN

BACKGROUND: The soluble urokinase plasminogen activator receptor (suPAR), a biomarker of inflammation, has been found to be a potential prognostic factor of renal function progression. Our previous study showed that plasma suPAR levels were significantly associated with disease activity and prognosis in patients with antineutrophil cytoplasmic autoantibody-associated vasculitis (AAV). OBJECTIVE: This study aimed to explore whether urokinase plasminogen activator receptor (uPAR) participated in MPO-ANCA-induced glomerular endothelial cell (GEnC) injury, which is one of the most important aspects in the pathogenesis of AAV. METHODS: GEnC activation and injury were analyzed by measuring the mRNA levels of ICAM-1 and VCAM-1. Permeability experiments were performed to detect endothelial monolayer activation in number. The expression of TLR4 was detected. In addition, TLR4 siRNA and TLR4 inhibitors were employed to determine its role. Bioinformatics methods were used for further analysis. RESULTS: Compared with a single stimulation, uPAR could further increase the expression of ICAM-1 and VCAM-1 mRNA levels, increase endothelial monolayer permeability and impair tight junctions in GEnCs stimulated with MPO-ANCA-positive IgG. The expression of TLR4 was upregulated by uPAR and MPO-ANCApositive IgG stimulation. TLR4 siRNA significantly reduced the expression of ICAM-1 and VCAM-1 mRNA levels induced by uPAR and MPO-ANCA-positive IgG. The TLR4 antagonist significantly downregulated the levels of ICAM-1 mRNA in cells and sICAM-1 in the supernatants of GEnCs treated with uPAR plus MPOANCA- positive IgG. PLAUR is a core gene in bioinformatics analysis. CONCLUSION: uPAR protein can enhance the GEnC activation and injury induced by MPO-ANCA-positive IgG through the TLR4 pathway, indicating that suPAR may be involved in the pathogenesis of AAV and that su- PAR might be regarded as a potential therapeutic target.


Asunto(s)
Anticuerpos Anticitoplasma de Neutrófilos , Vasculitis , Humanos , Receptores del Activador de Plasminógeno Tipo Uroquinasa/genética , Molécula 1 de Adhesión Intercelular , Receptor Toll-Like 4/genética , Molécula 1 de Adhesión Celular Vascular/genética , Inmunoglobulina G/farmacología , ARN Mensajero
17.
Int J Mol Sci ; 23(24)2022 Dec 19.
Artículo en Inglés | MEDLINE | ID: mdl-36555850

RESUMEN

Uncovering the risk factors for acute respiratory disease coronavirus 2019 (COVID-19) severity may help to provide a valuable tool for early patient stratification and proper treatment implementation, improving the patient outcome and lowering the burden on the healthcare system. Here we report the results of a single-center retrospective cohort study on 151 severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-infected symptomatic hospitalized adult patients. We assessed the association of several blood test measurements, soluble urokinase receptor (uPAR) serum level and specific single nucleotide polymorphisms of ACE (I/D), NOS3 (rs2070744, rs1799983), SERPINE1 (rs1799768), PLAU (rs2227564) and PLAUR (rs344781, rs2302524) genes, with the disease severity classified by the percentage of lung involvement on computerized tomography scans. Our findings reveal that the T/C genotype of PLAUR rs2302524 was independently associated with a less severe lung damage (odds ratio 0.258 [0.071-0.811]). Along with high C-reactive protein, fibrinogen and soluble uPAR serum levels turned out to be independently associated with more severe lung damage in COVID-19 patients. The identified factors may be further employed as predictors of a possibly severe COVID-19 clinical course.


Asunto(s)
COVID-19 , Pulmón , Receptores del Activador de Plasminógeno Tipo Uroquinasa , Adulto , Humanos , COVID-19/genética , Genotipo , Pulmón/patología , Receptores del Activador de Plasminógeno Tipo Uroquinasa/sangre , Receptores del Activador de Plasminógeno Tipo Uroquinasa/genética , Estudios Retrospectivos , SARS-CoV-2
18.
J Clin Invest ; 132(24)2022 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-36519539

RESUMEN

Atherosclerosis contributes to the majority of deaths related to cardiovascular disease (CVD). Recently, the nonspecific inflammatory biomarker soluble urokinase plasminogen activator receptor (suPAR) has shown prognostic value in patients with CVD; however, it remains unclear whether suPAR participates in the disease process. In this issue of the JCI, Hindy and colleagues report on their evaluation of a multi-ethnic cohort of over 5,000 participants without known CVD. High suPAR levels correlated with incident CVD and atherosclerosis. Genetic analysis revealed two variants associated with the suPAR-encoding gene (PLAUR) with higher plasma suPAR levels. Notably, a mouse model with high suPAR levels possessed aortic tissue with a proinflammatory phenotype, including monocytes with enhanced chemotaxis similar to that seen in atherogenesis. These findings suggest a causal relationship between suPAR and coronary artery calcification and have clinical implications that extend to inflammatory disorders beyond CVD.


Asunto(s)
Aterosclerosis , Enfermedades Cardiovasculares , Animales , Ratones , Humanos , Receptores del Activador de Plasminógeno Tipo Uroquinasa/genética , Enfermedades Cardiovasculares/genética , Factores de Riesgo , Biomarcadores , Aterosclerosis/genética
19.
Int J Mol Sci ; 23(22)2022 Nov 13.
Artículo en Inglés | MEDLINE | ID: mdl-36430487

RESUMEN

(-)-Epigallocatechin-3-O-gallate (EGCG), a primary green tea polyphenol, has powerful iron scavengers, belongs to the family of flavonoids with antioxidant properties, and can be used to prevent cancer. Urokinase-type plasminogen activator receptors (uPARs) are glycosylphosphatidylinositol (GPI)-anchored cell membrane receptors that have crucial roles in cell invasion and metastasis of several cancers including bladder cancer. The mechanism of action of EGCG on uPAR expression has not been reported clearly yet. In this study, we investigated the effect of EGCG on interleukin (IL)-1ß-induced cell invasion and uPAR activity in T24 human bladder cancer cells. Interestingly, nuclear factor (NF)-κB and activator protein (AP)-1 transcription factors were critically required for IL-1ß-induced high uPAR expression, and EGCG suppressed the transcriptional activity of both the ERK1/2 and JNK signaling pathways with the AP-1 subunit c-Jun. EGCG blocked the IL-1ß-stimulated reactive oxygen species (ROS) production, in turn suppressing NF-κB signaling and anti-invasion effects by inhibiting uPAR expression. These results suggest that EGCG may exert at least part of its anticancer effect by controlling uPAR expression through the suppression of ERK1/2, JNK, AP-1, and NF-κB.


Asunto(s)
Factor de Transcripción AP-1 , Neoplasias de la Vejiga Urinaria , Humanos , Factor de Transcripción AP-1/metabolismo , FN-kappa B/metabolismo , Receptores del Activador de Plasminógeno Tipo Uroquinasa/genética , Receptores del Activador de Plasminógeno Tipo Uroquinasa/metabolismo , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico
20.
J Clin Invest ; 132(24)2022 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-36194491

RESUMEN

People with kidney disease are disproportionately affected by atherosclerosis for unclear reasons. Soluble urokinase plasminogen activator receptor (suPAR) is an immune-derived mediator of kidney disease, levels of which are strongly associated with cardiovascular outcomes. We assessed suPAR's pathogenic involvement in atherosclerosis using epidemiologic, genetic, and experimental approaches. We found serum suPAR levels to be predictive of coronary artery calcification and cardiovascular events in 5,406 participants without known coronary disease. In a genome-wide association meta-analysis including over 25,000 individuals, we identified a missense variant in the plasminogen activator, urokinase receptor (PLAUR) gene (rs4760), confirmed experimentally to lead to higher suPAR levels. Mendelian randomization analysis in the UK Biobank using rs4760 indicated a causal association between genetically predicted suPAR levels and atherosclerotic phenotypes. In an experimental model of atherosclerosis, proprotein convertase subtilisin/kexin-9 (Pcsk9) transfection in mice overexpressing suPAR (suPARTg) led to substantially increased atherosclerotic plaques with necrotic cores and macrophage infiltration compared with those in WT mice, despite similar cholesterol levels. Prior to induction of atherosclerosis, aortas of suPARTg mice excreted higher levels of CCL2 and had higher monocyte counts compared with WT aortas. Aortic and circulating suPARTg monocytes exhibited a proinflammatory profile and enhanced chemotaxis. These findings characterize suPAR as a pathogenic factor for atherosclerosis acting at least partially through modulation of monocyte function.


Asunto(s)
Aterosclerosis , Receptores del Activador de Plasminógeno Tipo Uroquinasa , Animales , Ratones , Aterosclerosis/genética , Biomarcadores , Estudio de Asociación del Genoma Completo , Monocitos , Proproteína Convertasa 9 , Receptores del Activador de Plasminógeno Tipo Uroquinasa/genética , Factores de Riesgo , Activador de Plasminógeno de Tipo Uroquinasa , Humanos
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