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The membrane-anchored serine protease prostasin (CAP1\/PRSS8) is expressed in the distal nephron and participates in proteolytic ENaC regulation by serving as a scaffold for other serine proteases. However, it is unknown whether prostasin is also involved in ENaC-mediated sodium retention of experimental nephrotic syndrome. In this study, we used genetically modified knock-in mice with<jats:italic>Prss8<\/jats:italic>mutations abolishing its proteolytic activity (Prss8-S238A) or prostasin activation (Prss8-R44Q) to investigate the development of sodium retention in doxorubicin-induced nephrotic syndrome. Healthy Prss8-S238A and Prss8-R44Q mice had normal ENaC activity as reflected by the natriuretic response to the ENaC blocker triamterene. After doxorubicin injection, all genotypes developed similar proteinuria. In all genotypes, urinary prostasin excretion increased while renal expression was not altered. In nephrotic mice of all genotypes, triamterene response was similarly increased, consistent with ENaC activation. As a consequence, urinary sodium excretion dropped in all genotypes and mice similarly gained body weight by\u2009+\u200925\u2009\u00b1\u20093% in Prss8-wt,\u2009+\u200920\u2009\u00b1\u20092% in Prss8-S238A and\u2009+\u200928\u2009\u00b1\u20093% in Prss8-R44Q mice (<jats:italic>p<\/jats:italic>\u2009=\u20090.16). In Western blots, expression of fully cleaved \u03b1- and \u03b3-ENaC was similarly increased in nephrotic mice of all genotypes. In conclusion, proteolytic ENaC activation and sodium retention in experimental nephrotic syndrome are independent of the activation of prostasin and its enzymatic activity and are consistent with the action of aberrantly filtered serine proteases or proteasuria.<\/jats:p>","DOI":"10.1007\/s00424-022-02682-y","type":"journal-article","created":{"date-parts":[[2022,3,21]],"date-time":"2022-03-21T05:02:34Z","timestamp":1647838954000},"page":"613-624","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Sodium retention in nephrotic syndrome is independent of the activation of the membrane-anchored serine protease prostasin (CAP1\/PRSS8) and its enzymatic activity"],"prefix":"10.1007","volume":"474","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1473-377X","authenticated-orcid":false,"given":"Daniel","family":"Essigke","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0169-3948","authenticated-orcid":false,"given":"Bernhard N.","family":"Bohnert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Janessa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"W\u00f6rn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kingsley","family":"Omage","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hubert","family":"Kalbacher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas L.","family":"Birkenfeld","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas H.","family":"Bugge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roman","family":"Szabo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3777-9316","authenticated-orcid":false,"given":"Ferruh","family":"Artunc","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,3,21]]},"reference":[{"key":"2682_CR1","doi-asserted-by":"publisher","first-page":"1114","DOI":"10.1681\/ASN.V1261114","volume":"12","author":"M Adachi","year":"2001","unstructured":"Adachi M, Kitamura K, Miyoshi T, Narikiyo T, Iwashita K, Shiraishi N, Nonoguchi H, Tomita K (2001) Activation of epithelial sodium channels by prostasin in Xenopus oocytes. 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