{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T01:08:35Z","timestamp":1788916115500,"version":"build-2803163510"},"reference-count":35,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2018,3,25]],"date-time":"2018-03-25T00:00:00Z","timestamp":1521936000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["AR 1092\/2\u20101"],"award-info":[{"award-number":["AR 1092\/2\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Acta Physiologica"],"published-print":{"date-parts":[[2018,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Aim<\/jats:title><jats:p>Recent work has demonstrated that activation of the epithelial sodium channel (<jats:styled-content style=\"fixed-case\">EN<\/jats:styled-content>aC) by aberrantly filtered serine proteases causes sodium retention in nephrotic syndrome. The aim of this study was to elucidate a potential role of plasma kallikrein (<jats:styled-content style=\"fixed-case\">PKLK<\/jats:styled-content>) as a candidate serine protease in this context.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We analysed <jats:styled-content style=\"fixed-case\">PKLK<\/jats:styled-content> in the urine of patients with chronic kidney disease (<jats:styled-content style=\"fixed-case\">CKD<\/jats:styled-content>, n\u00a0=\u00a0171) and investigated its ability to activate human <jats:styled-content style=\"fixed-case\">EN<\/jats:styled-content>aC expressed in <jats:italic>Xenopus laevis<\/jats:italic> oocytes. Moreover, we studied sodium retention in <jats:styled-content style=\"fixed-case\">PKLK<\/jats:styled-content>\u2010deficient mice (<jats:italic>klkb1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>) with experimental nephrotic syndrome induced by doxorubicin injection.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In patients with <jats:styled-content style=\"fixed-case\">CKD<\/jats:styled-content>, we found that <jats:styled-content style=\"fixed-case\">PKLK<\/jats:styled-content> is excreted in the urine up to a concentration of 2\u00a0\u03bcg\u00a0mL<jats:sup>\u22121<\/jats:sup> which was correlated with albuminuria (<jats:italic>r<\/jats:italic>\u00a0=\u00a0.71) and overhydration as assessed by bioimpedance spectroscopy (<jats:italic>r<\/jats:italic>\u00a0=\u00a0.44). <jats:styled-content style=\"fixed-case\">PKLK<\/jats:styled-content> increased <jats:styled-content style=\"fixed-case\">EN<\/jats:styled-content>aC\u2010mediated whole\u2010cell currents, which was associated with the appearance of a 67\u00a0kDa \u03b3\u2010<jats:styled-content style=\"fixed-case\">EN<\/jats:styled-content>aC cleavage product at the cell surface consistent with proteolytic activation. Mutating a putative prostasin cleavage site in \u03b3\u2010<jats:styled-content style=\"fixed-case\">EN<\/jats:styled-content>aC prevented channel stimulation by <jats:styled-content style=\"fixed-case\">PKLK<\/jats:styled-content>. In a mouse model for nephrotic syndrome, active <jats:styled-content style=\"fixed-case\">PKLK<\/jats:styled-content> was present in nephrotic urine of <jats:italic>klkb1<\/jats:italic><jats:sup><jats:italic>+\/+<\/jats:italic><\/jats:sup> but not of <jats:italic>klkb1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice. However, <jats:italic>klkb1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice were not protected from <jats:styled-content style=\"fixed-case\">EN<\/jats:styled-content>aC activation and sodium retention compared to nephrotic <jats:italic>klkb1<\/jats:italic><jats:sup><jats:italic>+\/+<\/jats:italic><\/jats:sup> mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Plasma kallikrein is detected in the urine of proteinuric patients and mice and activates <jats:styled-content style=\"fixed-case\">EN<\/jats:styled-content>aC in\u00a0vitro involving the putative prostasin cleavage site. However, <jats:styled-content style=\"fixed-case\">PKLK<\/jats:styled-content> is not essential for volume retention in nephrotic mice.<\/jats:p><\/jats:sec>","DOI":"10.1111\/apha.13060","type":"journal-article","created":{"date-parts":[[2018,2,28]],"date-time":"2018-02-28T14:02:40Z","timestamp":1519826560000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Plasma kallikrein activates the epithelial sodium channel in\u00a0vitro but is not essential for volume retention in nephrotic mice"],"prefix":"10.1111","volume":"224","author":[{"given":"S.","family":"Haerteis","sequence":"first","affiliation":[{"name":"Institute of Cellular and Molecular Physiology Friedrich\u2010Alexander University Erlangen\u2010N\u00fcrnberg Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Schork","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry Department of Internal Medicine University Hospital T\u00fcbingen T\u00fcbingen Germany"},{"name":"Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich University of T\u00fcbingen T\u00fcbingen Germany"},{"name":"German Center for Diabetes Research (DZD) University of T\u00fcbingen T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T.","family":"D\u00f6rffel","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry Department of Internal Medicine University Hospital T\u00fcbingen T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B. 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