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The aim of this study was to explore the role of prostasin in proteolytic ENaC activation in the kidney in vivo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used genetically modified knockin mice carrying a Prss8 mutation abolishing proteolytic activity (Prss8\u2010S238A) or a mutation leading to a zymogen\u2010locked state (Prss8\u2010R44Q). Mice were challenged with low sodium diet and diuretics. Regulation of ENaC activity by Prss8\u2010S238A and Prss8\u2010R44Q was studied in vitro using the <jats:italic>Xenopus laevis<\/jats:italic> oocyte expression system.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Co\u2010expression of murine ENaC with Prss8\u2010wt or Prss8\u2010S238A in oocytes caused maximal proteolytic ENaC activation, whereas ENaC was activated only partially in oocytes co\u2010expressing Prss8\u2010R44Q. This was paralleled by a reduced proteolytic activity at the cell surface of Prss8\u2010R44Q expressing oocytes. Sodium conservation under low sodium diet was preserved in Prss8\u2010S238A and Prss8\u2010R44Q mice but with higher plasma aldosterone concentrations in Prss8\u2010R44Q mice. Treatment with the ENaC inhibitor triamterene over four days was tolerated in Prss8\u2010wt and Prss8\u2010S238A mice, whereas Prss8\u2010R44Q mice developed salt wasting and severe weight loss associated with hyperkalemia and acidosis consistent with impaired ENaC function and renal failure.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Unlike proteolytically inactive Prss8\u2010S238A, zymogen\u2010locked Prss8\u2010R44Q produces incomplete proteolytic ENaC activation in vitro and causes a severe renal phenotype in mice treated with the ENaC inhibitor triamterene. This indicates that Prss8 plays a role in proteolytic ENaC activation and renal function independent of its proteolytic activity.<\/jats:p><\/jats:sec>","DOI":"10.1111\/apha.13640","type":"journal-article","created":{"date-parts":[[2021,3,2]],"date-time":"2021-03-02T07:43:22Z","timestamp":1614671002000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Zymogen\u2010locked mutant prostasin (Prss8) leads to incomplete proteolytic activation of the epithelial sodium channel (ENaC) and severely compromises triamterene tolerance in mice"],"prefix":"10.1111","volume":"232","author":[{"given":"Daniel","family":"Essigke","sequence":"first","affiliation":[{"name":"Department of Internal Medicine Division of Endocrinology, Diabetology and Nephrology University Hospital T\u00fcbingen Tuebingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandr 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