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Plasmin is highly abundant in nephrotic urine and has been proposed to be the principal serine protease responsible for ENaC activation in NS. However, a proof of the essential role of plasmin in experimental NS is lacking.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used a genetic mouse model of NS based on an inducible podocin knockout (Bl6\u2010Nphs2<jats:sup>tm3.1Antc<\/jats:sup>*Tg(Nphs1\u2010rtTA*3G)<jats:sup>8Jhm<\/jats:sup>*Tg(tetO\u2010cre)<jats:sup>1Jaw<\/jats:sup> or <jats:italic>nphs2<jats:sup>\u0394ipod<\/jats:sup><\/jats:italic>). These mice were crossed with plasminogen deficient mice (Bl6\u2010Plg<jats:sup>tm1Jld<\/jats:sup> or plg<jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic>) to generate double knockout mice (<jats:italic>nphs2<jats:sup>\u0394ipod<\/jats:sup>*plg<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic>). NS was induced after oral doxycycline treatment for 14\u00a0days and mice were followed for subsequent 14\u00a0days.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Uninduced <jats:italic>nphs2<jats:sup>\u0394ipod<\/jats:sup>*plg<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mice had normal kidney function and sodium handling. After induction, proteinuria increased similarly in both <jats:italic>nphs2<jats:sup>\u0394ipod<\/jats:sup>*plg<jats:sup>+\/+<\/jats:sup><\/jats:italic> and <jats:italic>nphs2<jats:sup>\u0394ipod<\/jats:sup>*plg<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mice. Western blot revealed the urinary excretion of plasminogen and plasmin in <jats:italic>nphs2<jats:sup>\u0394ipod<\/jats:sup>*plg<jats:sup>+\/+<\/jats:sup><\/jats:italic> mice which were absent in <jats:italic>nphs2<jats:sup>\u0394ipod<\/jats:sup>*plg<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mice. After the onset of proteinuria, amiloride\u2010sensitive natriuresis was increased compared to the uninduced state in both genotypes. Subsequently, urinary sodium excretion dropped in both genotypes leading to an increase in body weight and development of ascites. Treatment with the serine protease inhibitor aprotinin prevented sodium retention in both genotypes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This study shows that mice lacking urinary plasminogen are not protected from ENaC\u2010mediated sodium retention in experimental NS. This points to an essential role of other urinary serine proteases in the absence of plasminogen.<\/jats:p><\/jats:sec>","DOI":"10.1111\/apha.13512","type":"journal-article","created":{"date-parts":[[2020,5,26]],"date-time":"2020-05-26T21:56:26Z","timestamp":1590530186000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Plasminogen deficiency does not prevent sodium retention in a genetic mouse model of experimental nephrotic syndrome"],"prefix":"10.1111","volume":"231","author":[{"given":"Mengyun","family":"Xiao","sequence":"first","affiliation":[{"name":"Department of Internal Medicine Division of Endocrinology, Diabetology and Nephrology University Hospital T\u00fcbingen T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernhard N.","family":"Bohnert","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Division of Endocrinology, Diabetology and Nephrology University Hospital T\u00fcbingen T\u00fcbingen Germany"},{"name":"Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University T\u00fcbingen T\u00fcbingen Germany"},{"name":"German Center for Diabetes Research (DZD) at the University T\u00fcbingen T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hande","family":"Aypek","sequence":"additional","affiliation":[{"name":"III. 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Department of Medicine, Faculty and University Medical Center Freiburg Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"W\u00f6rn","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Division of Endocrinology, Diabetology and Nephrology University Hospital T\u00fcbingen T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Janessa","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Division of Endocrinology, Diabetology and Nephrology University Hospital T\u00fcbingen T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Essigke","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Division of Endocrinology, Diabetology and Nephrology University Hospital T\u00fcbingen T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Daniel","sequence":"additional","affiliation":[{"name":"Institute of Nephropathology Friedrich\u2010Alexander University Erlangen\u2010N\u00fcrnberg (FAU) Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerstin","family":"Amann","sequence":"additional","affiliation":[{"name":"Institute of Nephropathology Friedrich\u2010Alexander University Erlangen\u2010N\u00fcrnberg (FAU) Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias B.","family":"Huber","sequence":"additional","affiliation":[{"name":"III. 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