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J Biol Chem
2015 Feb 27;2909:5241-55. doi: 10.1074/jbc.M114.623496.
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Proteolytic regulation of epithelial sodium channels by urokinase plasminogen activator: cutting edge and cleavage sites.
Ji HL
,
Zhao R
,
Komissarov AA
,
Chang Y
,
Liu Y
,
Matthay MA
.
???displayArticle.abstract??? Plasminogen activator inhibitor 1 (PAI-1) level is extremely elevated in the edematous fluid of acutely injured lungs and pleurae. Elevated PAI-1 specifically inactivates pulmonary urokinase-type (uPA) and tissue-type plasminogen activators (tPA). We hypothesized that plasminogen activation and fibrinolysis may alter epithelial sodium channel (ENaC) activity, a key player in clearing edematous fluid. Two-chain urokinase (tcuPA) has been found to strongly stimulate heterologous human αβγ ENaC activity in a dose- and time-dependent manner. This activity of tcuPA was completely ablated by PAI-1. Furthermore, a mutation (S195A) of the active site of the enzyme also prevented ENaC activation. By comparison, three truncation mutants of the amino-terminal fragment of tcuPA still activated ENaC. uPA enzymatic activity was positively correlated with ENaC current amplitude prior to reaching the maximal level. In sharp contrast to uPA, neither single-chain tPA nor derivatives, including two-chain tPA and tenecteplase, affected ENaC activity. Furthermore, γ but not α subunit of ENaC was proteolytically cleaved at ((177)GR↓KR(180)) by tcuPA. In summary, the underlying mechanisms of urokinase-mediated activation of ENaC include release of self-inhibition, proteolysis of γ ENaC, incremental increase in opening rate, and activation of closed (electrically "silent") channels. This study for the first time demonstrates multifaceted mechanisms for uPA-mediated up-regulation of ENaC, which form the cellular and molecular rationale for the beneficial effects of urokinase in mitigating mortal pulmonary edema and pleural effusions.
Bertozzi,
Depressed bronchoalveolar urokinase activity in patients with adult respiratory distress syndrome.
1990, Pubmed
Bertozzi,
Depressed bronchoalveolar urokinase activity in patients with adult respiratory distress syndrome.
1990,
Pubmed
Bhattacharya,
Regulation and repair of the alveolar-capillary barrier in acute lung injury.
2013,
Pubmed
Bouros,
Intrapleural urokinase in the treatment of complicated parapneumonic pleural effusions and empyema.
1996,
Pubmed
Caldwell,
Neutrophil elastase activates near-silent epithelial Na+ channels and increases airway epithelial Na+ transport.
2005,
Pubmed
Caldwell,
Serine protease activation of near-silent epithelial Na+ channels.
2004,
Pubmed
Chapman,
Abnormalities in pathways of alveolar fibrin turnover among patients with interstitial lung disease.
1986,
Pubmed
Chen,
Influenza virus inhibits ENaC and lung fluid clearance.
2004,
Pubmed
Chen,
Regulation of epithelial sodium channels in urokinase plasminogen activator deficiency.
2014,
Pubmed
,
Xenbase
Chraïbi,
Na self inhibition of human epithelial Na channel: temperature dependence and effect of extracellular proteases.
2002,
Pubmed
,
Xenbase
Coombs,
Directing sequence-specific proteolysis to new targets. The influence of loop size and target sequence on selective proteolysis by tissue-type plasminogen activator and urokinase-type plasminogen activator.
1998,
Pubmed
Crippa,
Urokinase-type plasminogen activator.
2007,
Pubmed
Dagenais,
Modulation of epithelial sodium channel (ENaC) expression in mouse lung infected with Pseudomonas aeruginosa.
2005,
Pubmed
Davis,
Epithelial sodium channels in the adult lung--important modulators of pulmonary health and disease.
2007,
Pubmed
Diakov,
Cleavage in the {gamma}-subunit of the epithelial sodium channel (ENaC) plays an important role in the proteolytic activation of near-silent channels.
2008,
Pubmed
,
Xenbase
Ding,
Origins of the specificity of tissue-type plasminogen activator.
1995,
Pubmed
Eaton,
The contribution of epithelial sodium channels to alveolar function in health and disease.
2009,
Pubmed
Fuller,
Kinetic interconversion of rat and bovine homologs of the alpha subunit of an amiloride-sensitive Na+ channel by C-terminal truncation of the bovine subunit.
1996,
Pubmed
,
Xenbase
García-Caballero,
ENaC proteolytic regulation by channel-activating protease 2.
2008,
Pubmed
Glas,
Bronchoalveolar hemostasis in lung injury and acute respiratory distress syndrome.
2013,
Pubmed
Goldfarb,
Differential effects of Hsc70 and Hsp70 on the intracellular trafficking and functional expression of epithelial sodium channels.
2006,
Pubmed
,
Xenbase
Gonzales,
Pore architecture and ion sites in acid-sensing ion channels and P2X receptors.
2009,
Pubmed
Gross,
Expression of urokinase-type plasminogen activator by rat pulmonary alveolar epithelial cells.
1990,
Pubmed
Günther,
Prevention of bleomycin-induced lung fibrosis by aerosolization of heparin or urokinase in rabbits.
2003,
Pubmed
Haerteis,
The delta-subunit of the epithelial sodium channel (ENaC) enhances channel activity and alters proteolytic ENaC activation.
2009,
Pubmed
,
Xenbase
Haerteis,
Plasmin and chymotrypsin have distinct preferences for channel activating cleavage sites in the γ subunit of the human epithelial sodium channel.
2012,
Pubmed
,
Xenbase
Hochberg,
Patterns of alveolar fluid clearance in heart failure.
2008,
Pubmed
Huang,
Tissue plasminogen activator attenuates ventilator-induced lung injury in rats.
2012,
Pubmed
Hummler,
Importance of ENaC-mediated sodium transport in alveolar fluid clearance using genetically-engineered mice.
2010,
Pubmed
Idell,
Local abnormalities in coagulation and fibrinolytic pathways predispose to alveolar fibrin deposition in the adult respiratory distress syndrome.
1989,
Pubmed
Idell,
Abnormalities of pathways of fibrin turnover in the human pleural space.
1991,
Pubmed
Idell,
Serial abnormalities of fibrin turnover in evolving adult respiratory distress syndrome.
1991,
Pubmed
Idell,
Pathways of fibrin turnover of human pleural mesothelial cells in vitro.
1992,
Pubmed
Idell,
Fibrinolytic activity in bronchoalveolar lavage of baboons with diffuse alveolar damage: trends in two forms of lung injury.
1992,
Pubmed
Idell,
Intrapleural activation, processing, efficacy, and duration of protection of single-chain urokinase in evolving tetracycline-induced pleural injury in rabbits.
2007,
Pubmed
Idell,
Intrapleural low-molecular-weight urokinase or tissue plasminogen activator versus single-chain urokinase in tetracycline-induced pleural loculation in rabbits.
2007,
Pubmed
Idell,
The pathogenesis of pleural space loculation and fibrosis.
2008,
Pubmed
Jasti,
Structure of acid-sensing ion channel 1 at 1.9 A resolution and low pH.
2007,
Pubmed
Ji,
Degenerin sites mediate proton activation of deltabetagamma-epithelial sodium channel.
2004,
Pubmed
,
Xenbase
Ji,
δ ENaC: a novel divergent amiloride-inhibitable sodium channel.
2012,
Pubmed
Ji,
Delta-subunit confers novel biophysical features to alpha beta gamma-human epithelial sodium channel (ENaC) via a physical interaction.
2006,
Pubmed
Ji,
Peptide inhibition of constitutively activated epithelial Na(+) channels expressed in Xenopus oocytes.
1999,
Pubmed
,
Xenbase
Ji,
Point mutations in the post-M2 region of human alpha-ENaC regulate cation selectivity.
2001,
Pubmed
,
Xenbase
Ke,
Distinguishing the specificities of closely related proteases. Role of P3 in substrate and inhibitor discrimination between tissue-type plasminogen activator and urokinase.
1997,
Pubmed
Ke,
Optimal subsite occupancy and design of a selective inhibitor of urokinase.
1997,
Pubmed
Kleyman,
ENaC at the cutting edge: regulation of epithelial sodium channels by proteases.
2009,
Pubmed
Knight,
Intracellular sodium regulates proteolytic activation of the epithelial sodium channel.
2008,
Pubmed
Komissarov,
Active α-macroglobulin is a reservoir for urokinase after fibrinolytic therapy in rabbits with tetracycline-induced pleural injury and in human pleural fluids.
2013,
Pubmed
Komissarov,
Regulation of intrapleural fibrinolysis by urokinase-alpha-macroglobulin complexes in tetracycline-induced pleural injury in rabbits.
2009,
Pubmed
Kotani,
Increased procoagulant and antifibrinolytic activities in the lungs with idiopathic pulmonary fibrosis.
1995,
Pubmed
Kunzelmann,
Influenza virus inhibits amiloride-sensitive Na+ channels in respiratory epithelia.
2000,
Pubmed
Kuramoto,
Inhalation of urokinase-type plasminogen activator reduces airway remodeling in a murine asthma model.
2009,
Pubmed
Kvassman,
The acid stabilization of plasminogen activator inhibitor-1 depends on protonation of a single group that affects loop insertion into beta-sheet A.
1995,
Pubmed
Lee,
Treatment of thoracic multiloculated empyemas with intracavitary urokinase: a prospective study.
1991,
Pubmed
MacLaren,
Stress-dose corticosteroid therapy for sepsis and acute lung injury or acute respiratory distress syndrome in critically ill adults.
2002,
Pubmed
Madison,
Substrate specificity of tissue type plasminogen activator. Characterization of the fibrin independent specificity of t-PA for plasminogen.
1995,
Pubmed
Maron,
Beta-adrenoceptor stimulation of alveolar fluid clearance is increased in rats with heart failure.
2009,
Pubmed
Marshall,
Alveolar epithelial cell plasminogen activator. Characterization and regulation.
1990,
Pubmed
Matthay,
Resolution of pulmonary edema. Thirty years of progress.
2014,
Pubmed
Matthay,
Lung epithelial fluid transport and the resolution of pulmonary edema.
2002,
Pubmed
Miyake,
Elevation of serum levels of urokinase-type plasminogen activator and its receptor is associated with disease progression and prognosis in patients with prostate cancer.
1999,
Pubmed
Molina,
Cpt-cAMP activates human epithelial sodium channels via relieving self-inhibition.
2011,
Pubmed
,
Xenbase
Münster,
Jet and ultrasonic nebulization of single chain urokinase plasminogen activator (scu-PA).
2000,
Pubmed
Nishiuma,
Localization of plasminogen activator activity within normal and injured lungs by in situ zymography.
2004,
Pubmed
Passero,
Plasmin activates epithelial Na+ channels by cleaving the gamma subunit.
2008,
Pubmed
,
Xenbase
Pechlaner,
Plasminogen activators in inflammation and sepsis.
2002,
Pubmed
Planès,
Regulation of the epithelial Na+ channel by peptidases.
2007,
Pubmed
,
Xenbase
Prabhakaran,
Elevated levels of plasminogen activator inhibitor-1 in pulmonary edema fluid are associated with mortality in acute lung injury.
2003,
Pubmed
Renckens,
Transgenic tissue-type plasminogen activator expression improves host defense during Klebsiella pneumonia.
2008,
Pubmed
Rossier,
Activation of the epithelial sodium channel (ENaC) by serine proteases.
2009,
Pubmed
Rossier,
The epithelial sodium channel: activation by membrane-bound serine proteases.
2004,
Pubmed
Sapru,
Elevated PAI-1 is associated with poor clinical outcomes in pediatric patients with acute lung injury.
2010,
Pubmed
Schermuly,
Conebulization of surfactant and urokinase restores gas exchange in perfused lungs with alveolar fibrin formation.
2001,
Pubmed
Schuliga,
The plasminogen activation system: new targets in lung inflammation and remodeling.
2013,
Pubmed
Sheng,
Extracellular Zn2+ activates epithelial Na+ channels by eliminating Na+ self-inhibition.
2004,
Pubmed
,
Xenbase
Sheng,
Functional role of extracellular loop cysteine residues of the epithelial Na+ channel in Na+ self-inhibition.
2007,
Pubmed
,
Xenbase
Sherwood,
Structure and activity of the acid-sensing ion channels.
2012,
Pubmed
Shetty,
The fibrinolytic system and the regulation of lung epithelial cell proteolysis, signaling, and cellular viability.
2008,
Pubmed
Sisson,
Inducible lung-specific urokinase expression reduces fibrosis and mortality after lung injury in mice.
2002,
Pubmed
Sisson,
The plasminogen activation system in lung disease.
2007,
Pubmed
Stewart,
Identification of the mechanism responsible for the increased fibrin specificity of TNK-tissue plasminogen activator relative to tissue plasminogen activator.
2000,
Pubmed
Strange,
Effects of intrapleural heparin or urokinase on the extent of tetracycline-induced pleural disease.
1995,
Pubmed
Stringer,
Tissue plasminogen activator (tPA) inhibits interleukin-1 induced acute lung leak.
1998,
Pubmed
Stringer,
Administration of exogenous tissue plasminogen activator reduces oedema in mice lacking the tissue plasminogen activator gene.
2004,
Pubmed
Takahashi,
Lung capillary endothelial cells produce and secrete urokinase-type plasminogen activator.
1992,
Pubmed
Verspurten,
SitePredicting the cleavage of proteinase substrates.
2009,
Pubmed
Viscardi,
Disordered pathways of fibrin turnover in lung lavage of premature infants with respiratory distress syndrome.
1992,
Pubmed
Ware,
Clinical practice. Acute pulmonary edema.
2005,
Pubmed
Ware,
Bench to bedside: targeting coagulation and fibrinolysis in acute lung injury.
2006,
Pubmed
Zeslawska,
Crystals of urokinase type plasminogen activator complexes reveal the binding mode of peptidomimetic inhibitors.
2003,
Pubmed
Šedý,
Mechanisms of neurogenic pulmonary edema development.
2008,
Pubmed
