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Targeted and efficient pharmaceutical therapy of elevated ICP is not currently available, as the molecular mechanisms governing cerebrospinal fluid (CSF) secretion are largely unresolved. To resolve the quantitative contribution of key choroid plexus transport proteins, this study employs mice with genetic knockout and\/or viral choroid plexus\u2010specific knockdown of aquaporin 1 (AQP1) and the Na\n                    <jats:sup>+<\/jats:sup>\n                    , K\n                    <jats:sup>+<\/jats:sup>\n                    , 2Cl\n                    <jats:sup>\u2212<\/jats:sup>\n                    cotransporter 1 (NKCC1) for in vivo determinations of CSF dynamics, ex vivo choroid plexus for transporter\u2010mediated clearance of a CSF K\n                    <jats:sup>+<\/jats:sup>\n                    load, and patient CSF for [K\n                    <jats:sup>+<\/jats:sup>\n                    ] quantification. CSF secretion and ICP management occur independently of choroid plexus AQP1 expression, whereas both parameters are reduced by 40% upon choroid plexus NKCC1 knockdown. Elevation of [K\n                    <jats:sup>+<\/jats:sup>\n                    ]\n                    <jats:sub>CSF<\/jats:sub>\n                    increases the choroid plexus Na\n                    <jats:sup>+<\/jats:sup>\n                    \/K\n                    <jats:sup>+<\/jats:sup>\n                    \u2010ATPase activity, and favors inwardly\u2010directed net NKCC1 transport, which, together, promote CSF K\n                    <jats:sup>+<\/jats:sup>\n                    clearance, while maintaining undisturbed CSF secretion rates. CSF from patients with post\u2010hemorrhagic hydrocephalus does not display elevated [K\n                    <jats:sup>+<\/jats:sup>\n                    ]\n                    <jats:sub>CSF<\/jats:sub>\n                    , suggesting that NKCC1 maintains net outward transport direction during post\u2010hemorrhagic hydrocephalus formation. Direct or indirect therapeutic modulation of choroid plexus NKCC1 can thus be a potential promising pharmacological approach against brain pathologies associated with elevated ICP.\n                  <\/jats:p>","DOI":"10.1002\/advs.202409120","type":"journal-article","created":{"date-parts":[[2024,12,18]],"date-time":"2024-12-18T10:39:56Z","timestamp":1734518396000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["The Na\n                    <sup>+<\/sup>\n                    ,K\n                    <sup>+<\/sup>\n                    ,2Cl\n                    <sup>\u2212<\/sup>\n                    Cotransporter, Not Aquaporin 1, Sustains Cerebrospinal Fluid Secretion While Controlling Brain K\n                    <sup>+<\/sup>\n                    Homeostasis"],"prefix":"10.1002","volume":"12","author":[{"given":"Dennis Bo","family":"Jensen","sequence":"first","affiliation":[{"name":"Department of Neuroscience University of Copenhagen  Blegdamsvej 3 Copenhagen N 2200 Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trine L.","family":"Toft\u2010Bertelsen","sequence":"additional","affiliation":[{"name":"Department of Neuroscience University of Copenhagen  Blegdamsvej 3 Copenhagen N 2200 Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dagne","family":"Barbuskaite","sequence":"additional","affiliation":[{"name":"Department of Neuroscience University of Copenhagen  Blegdamsvej 3 Copenhagen N 2200 Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane","family":"Stubbe","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine University of Southern Denmark  Campusvej 55 Odense 5230 Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandor","family":"Nietzsche","sequence":"additional","affiliation":[{"name":"Center for Electron Microscopy Jena University Hospital  Ziegelm\u00fchlenweg 1 07743 Jena Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tenna","family":"Capion","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery University Hospital of Copenhagen \u2013 Rigshospitalet  Blegdamsvej 9 Copenhagen 2100 Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas H.","family":"Norager","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery University Hospital of Copenhagen \u2013 Rigshospitalet  Blegdamsvej 9 Copenhagen 2100 Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus H.","family":"Olsen","sequence":"additional","affiliation":[{"name":"Department of Neuroanaesthesiology University Hospital of Copenhagen \u2013 Rigshospitalet  Blegdamsvej 9 Copenhagen 2100 Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas T.","family":"S\u00f8rensen","sequence":"additional","affiliation":[{"name":"Department of Neuroscience University of Copenhagen  Blegdamsvej 3 Copenhagen N 2200 Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrik","family":"Dimke","sequence":"additional","affiliation":[{"name":"Department of Nephrology Odense University Hospital  J.B. 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