ArticleThe Journal of biological chemistry2015
Proteolytic regulation of epithelial sodium channels by urokinase plasminogen activator: cutting edge and cleavage sites.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers, 2 of them syntheses that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
25 citing papers in PubMed, 2 syntheses or guidelines pooled it, 41 citations in OpenAlex.
- Meta-Analysis of Preclinical Studies of Fibrinolytic Therapy for Acute Lung Injury.Frontiers in immunology · 2018Pooled it
- Systematic review and meta-analysis of nasal potential difference in hypoxia-induced lung injury.Scientific reports · 2016Pooled it
- Influence of proteolytic cleavage of ENaC's γ subunit upon NaAmerican journal of physiology. Renal physiology · 2024Article
- Epithelial NaComprehensive Physiology · 2024Review
- PAI-1 regulates AT2-mediated re-alveolarization and ion permeability.Stem cell research & therapy · 2023Article
- Fibrinolytic system and COVID-19: From an innovative view of epithelial ion transport.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2023Review
- PAI-1 regulates AT2-mediated re-alveolarization and ion permeability.Research square · 2023Article
- ENaC activation by proteases.Acta physiologica (Oxford, England) · 2022Review
- Fibrinolytic or anti-plasmin (nafamostat) therapy for COVID-19: A timing challenge for clinicians.Pulmonary pharmacology & therapeutics · 2021Article
- Urinary proteomics reveals key markers of salt sensitivity in hypertensive patients during saline infusion.Journal of nephrology · 2021Article
- Fibrinolytic niche is required for alveolar type 2 cell-mediated alveologenesis via a uPA-A6-CD44Signal transduction and targeted therapy · 2021Article
- Conditioned Medium of Bone Marrow Mesenchymal Stem Cells Involved in Acute Lung Injury by Regulating Epithelial Sodium ChannelsFrontiers in bioengineering and biotechnology · 2021Article
- ENaC in Salt-Sensitive Hypertension: Kidney and Beyond.Current hypertension reports · 2020Review
- Plasmin improves blood-gas barrier function in oedematous lungs by cleaving epithelial sodium channels.British journal of pharmacology · 2020Article
- Elevated Plasmin(ogen) as a Common Risk Factor for COVID-19 Susceptibility.Physiological reviews · 2020Review
- Regulating ENaC's gate.American journal of physiology. Cell physiology · 2020Review
- New insights regarding epithelial Na+ channel regulation and its role in the kidney, immune system and vasculature.Current opinion in nephrology and hypertension · 2019Review
- Article
- Alveolar type 2 progenitor cells for lung injury repair.Cell death discovery · 2019Review
- Excretory/secretory proteases and mechanical movement of Anisakis pegreffii infective larvae in the penetration of BALB/c mice gastrointestine.The Kaohsiung journal of medical sciences · 2017Article
Corrections and comments
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Authors and funding
6 authors at 4 institutions in 2 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.