{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T20:46:04Z","timestamp":1786135564342,"version":"build-2736575974"},"reference-count":69,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2024,10,23]],"date-time":"2024-10-23T00:00:00Z","timestamp":1729641600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"crossref","award":["509149993 (TRR 374; subproject A4)"],"award-info":[{"award-number":["509149993 (TRR 374; subproject A4)"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"crossref","award":["509149993 (TRR 374; subproject A4)"],"award-info":[{"award-number":["509149993 (TRR 374; subproject A4)"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"crossref","award":["509149993 (TRR 374; subproject B1)"],"award-info":[{"award-number":["509149993 (TRR 374; subproject B1)"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"crossref","award":["493665037 (MINT-Clinician Scientist program of the Medical Faculty T\u00c3\u00bcbingen)"],"award-info":[{"award-number":["493665037 (MINT-Clinician Scientist program of the Medical Faculty T\u00c3\u00bcbingen)"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"crossref","award":["457011590"],"award-info":[{"award-number":["457011590"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Bayerisches Staatsministerium f\u00c3\u00bcr Wissenschaft und Kunst","award":["project VI-Corona-Forschung (subproject 07)"],"award-info":[{"award-number":["project VI-Corona-Forschung (subproject 07)"]}]},{"name":"Bayerisches Staatsministerium f\u00c3\u00bcr Wissenschaft und Kunst","award":["project VI-Corona-Forschung (subproject 07)"],"award-info":[{"award-number":["project VI-Corona-Forschung (subproject 07)"]}]},{"name":"Interdisziplin\u00c3\u00a4res Zentrum f\u00c3\u00bcr klinische Forschung (IZKF) Erlangen","award":["MD-Thesis Scholarship"],"award-info":[{"award-number":["MD-Thesis Scholarship"]}]},{"name":"IZKF program of the Medical Faculty T\u00c3\u00bcbingen"},{"name":"Bundesministerium f\u00c3\u00bcr Bildung und Forschung","award":["SENSE-CoV2, 01KI20172A"],"award-info":[{"award-number":["SENSE-CoV2, 01KI20172A"]}]}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["JASN"],"published-print":{"date-parts":[[2025,3]]},"abstract":"\n Key Points<\/jats:title>\n \n \n \n Proteolytic activation of the epithelial sodium channel (ENaC) was compromised by transmembrane serine protease 2 deficiency in murine cortical collecting duct cells and native mouse kidney.<\/jats:p>\n <\/jats:list-item>\n \n \n To compensate for impaired ENaC activation, rise in plasma aldosterone in response to low-salt diet was enhanced in\n Tmprss2<\/jats:italic>\n \u2212\/\u2212<\/jats:sup>\n mice.\n <\/jats:p>\n <\/jats:list-item>\n \n Transmembrane serine protease 2 may be a potential drug target to limit proteolytic ENaC activation in disorders with increased renal ENaC activity.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>\n \n Background<\/jats:title>\n The renal epithelial sodium channel (ENaC) is essential for sodium balance and BP control. ENaC undergoes complex proteolytic activation by not yet clearly identified tubular proteases. Here, we examined a potential role of transmembrane serine protease 2 (TMPRSS2).<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Murine ENaC and TMPRSS2 were (co)expressed in\n Xenopus laevis<\/jats:italic>\n oocytes. ENaC cleavage and function were studied in TMPRSS2-deficient murine cortical collecting duct (mCCD\n cl1<\/jats:sub>\n ) cells and TMPRSS2-knockout (\n Tmprss2<\/jats:italic>\n \u2212\/\u2212<\/jats:sup>\n ) mice. Short-circuit currents (\n I<\/jats:italic>\n SC<\/jats:sub>\n ) were measured to assess ENaC-mediated transepithelial sodium transport of mCCD\n cl1<\/jats:sub>\n cells. The mCCD\n cl1<\/jats:sub>\n cell transcriptome was studied using RNA sequencing. The effect of low-sodium diet with or without high potassium were compared in\n Tmprss2<\/jats:italic>\n \u2212\/\u2212<\/jats:sup>\n and wild-type mice using metabolic cages. ENaC-mediated whole-cell currents were recorded from microdissected tubules of\n Tmprss2<\/jats:italic>\n \u2212\/\u2212<\/jats:sup>\n and wild-type mice.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n In oocytes, coexpression of murine TMPRSS2 and ENaC resulted in fully cleaved\n \u03b3<\/jats:italic>\n -ENaC and approximately two-fold stimulation of ENaC currents. High baseline expression of TMPRSS2 was detected in mCCD\n cl1<\/jats:sub>\n cells without a stimulatory effect of aldosterone on its function or transcription. TMPRSS2 knockout in mCCD\n cl1<\/jats:sub>\n cells compromised\n \u03b3<\/jats:italic>\n -ENaC cleavage and reduced baseline and aldosterone-stimulated\n I<\/jats:italic>\n SC<\/jats:sub>\n , which could be rescued by chymotrypsin. A compensatory transcriptional upregulation of other proteases was not observed.\n Tmprss2<\/jats:italic>\n \u2212\/\u2212<\/jats:sup>\n mice kept on standard diet exhibited no apparent phenotype, but renal\n \u03b3<\/jats:italic>\n -ENaC cleavage was altered. In response to a low-salt diet, particularly with high potassium intake,\n Tmprss2<\/jats:italic>\n \u2212\/\u2212<\/jats:sup>\n mice increased plasma aldosterone significantly more than wild-type mice to achieve a similar reduction of renal sodium excretion. Importantly, the stimulatory effect of trypsin on renal tubular ENaC currents was much more pronounced in\n Tmprss2<\/jats:italic>\n \u2212\/\u2212<\/jats:sup>\n mice than that in wild-type mice. This indicated the presence of incompletely cleaved and less active channels at the cell surface of TMPRSS2-deficient tubular epithelial cells.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n TMPRSS2 contributes to proteolytic ENaC activation in mouse kidney\n in vivo<\/jats:italic>\n .\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1681\/asn.0000000521","type":"journal-article","created":{"date-parts":[[2024,10,23]],"date-time":"2024-10-23T12:04:09Z","timestamp":1729685049000},"page":"420-434","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":10,"title":["Transmembrane Serine Protease 2 and Proteolytic Activation of the Epithelial Sodium Channel in Mouse Kidney"],"prefix":"10.1681","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2255-5571","authenticated-orcid":false,"given":"Florian","family":"Sure","sequence":"first","affiliation":[{"name":"Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg, Institute of Cellular and Molecular Physiology, Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Afonso","sequence":"additional","affiliation":[{"name":"Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg, Institute of Cellular and Molecular Physiology, Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1473-377X","authenticated-orcid":false,"given":"Daniel","family":"Essigke","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetology and Nephrology, 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 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":"Paul","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetology and Nephrology, Department of Internal Medicine, University Hospital T\u00fcbingen, T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Zaher","family":"Kalo","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetology and Nephrology, Department of Internal Medicine, University Hospital T\u00fcbingen, T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viatcheslav","family":"Nesterov","sequence":"additional","affiliation":[{"name":"Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg, Institute of Cellular and Molecular Physiology, Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4287-0756","authenticated-orcid":false,"given":"Alicia","family":"Ki\u00dfler","sequence":"additional","affiliation":[{"name":"Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg, Institute of Cellular and Molecular Physiology, Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1504-9582","authenticated-orcid":false,"given":"Marko","family":"Bertog","sequence":"additional","affiliation":[{"name":"Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg, Institute of Cellular and Molecular Physiology, Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3063-0519","authenticated-orcid":false,"given":"Ralf","family":"Rinke","sequence":"additional","affiliation":[{"name":"Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg, Institute of Cellular and Molecular Physiology, Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine","family":"Wittmann","sequence":"additional","affiliation":[{"name":"Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg, Institute of Clinical and Molecular Virology, Universit\u00e4tsklinikum Erlangen, Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5937-6756","authenticated-orcid":false,"given":"Katharina A.E.","family":"Broeker","sequence":"additional","affiliation":[{"name":"Institute of Physiology, University of Regensburg, Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5507-6721","authenticated-orcid":false,"given":"Thomas","family":"Gramberg","sequence":"additional","affiliation":[{"name":"Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg, Institute of Clinical and Molecular Virology, Universit\u00e4tsklinikum Erlangen, Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3777-9316","authenticated-orcid":false,"given":"Ferruh","family":"Artunc","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetology and Nephrology, 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 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"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2127-4185","authenticated-orcid":false,"given":"Christoph","family":"Korbmacher","sequence":"additional","affiliation":[{"name":"Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg, Institute of Cellular and Molecular Physiology, Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2153-7849","authenticated-orcid":false,"given":"Alexandr V.","family":"Ilyaskin","sequence":"additional","affiliation":[{"name":"Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg, Institute of Cellular and Molecular 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