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This concept predicts that uPA is an important factor for sodium retention and that inhibition of uPA might be protective in nephrotic syndrome.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Activation of amiloride\u2010sensitive currents by uPA and plg were studied in <jats:italic>Xenopus laevis<\/jats:italic> oocytes expressing murine ENaC. In doxorubicin\u2010induced nephrotic mice, uPA was inhibited pharmacologically by amiloride and genetically by the use of uPA\u2010deficient mice (<jats:italic>uPA<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Experiments in <jats:italic>Xenopus laevis<\/jats:italic> oocytes expressing murine ENaC confirmed proteolytic ENaC activation by a combination of plg and uPA which stimulated amiloride\u2010sensitive currents with concomitant cleavage of the ENaC \u03b3\u2010subunit at the cell surface. Treatment of nephrotic wild\u2010type mice with amiloride inhibited urinary uPA activity, prevented urinary plasmin formation and sodium retention. In nephrotic mice lacking uPA (<jats:italic>uPA<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic>), urinary plasmin formation from plg was suppressed and urinary uPA activity absent. However, in nephrotic <jats:italic>uPA<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mice, sodium retention was not reduced compared to nephrotic <jats:italic>uPA<jats:sup>+\/+<\/jats:sup><\/jats:italic> mice. Amiloride prevented sodium retention in nephrotic <jats:italic>uPA<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mice which confirmed the critical role of ENaC in sodium retention.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>uPA is responsible for the conversion of aberrantly filtered plasminogen to plasmin in the tubular lumen in vivo. However, uPA\u2010dependent plasmin generation is not essential for ENaC\u2010mediated sodium retention in experimental nephrotic syndrome.<\/jats:p><\/jats:sec>","DOI":"10.1111\/apha.13286","type":"journal-article","created":{"date-parts":[[2019,4,21]],"date-time":"2019-04-21T13:43:57Z","timestamp":1555854237000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":51,"title":["Urokinase\u2010type plasminogen activator (uPA) is not essential for epithelial sodium channel (ENaC)\u2010mediated sodium retention in experimental nephrotic syndrome"],"prefix":"10.1111","volume":"227","author":[{"given":"Bernhard N.","family":"Bohnert","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry University Hospital T\u00fcbingen T\u00fcbingen Germany"},{"name":"Institute of Diabetes Research and Metabolic Diseases (IDM) of the 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