{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T19:24:21Z","timestamp":1783625061777,"version":"3.55.0"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,10,21]],"date-time":"2024-10-21T00:00:00Z","timestamp":1729468800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>Regulation of cerebrospinal fluid (CSF) pH and brain pH are vital for all brain cells. The acute regulation of CSF pH is dependent on the transport of HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> across the choroid plexus in the brain ventricles. Acute regulation in response to acidosis is dependent on H<jats:sup>+<\/jats:sup> export and HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> import across the plasma membrane. Acute regulation in response to alkalosis is dependent on HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> export across the plasma membrane. The objective of the study was to investigate the contribution of the Na<jats:sup>+<\/jats:sup>-dependent HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> transporters, Ncbe, NBCn1, and NBCe2 to CSF pH regulation during chronic metabolic acidosis in mice. To induce metabolic acidosis, mice received 0.28 M ammonium chloride (NH<jats:sub>4<\/jats:sub>Cl) in the drinking water for three, five, or seven days. While <jats:italic>in vivo,<\/jats:italic> CSF pH measurements did not differ, measurements of CSF [HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup>] revealed a significantly lower CSF [HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup>] after three days of acid-loading. Immunoblotting of choroid plexus protein samples showed that the abundance of the basolateral Na<jats:sup>+<\/jats:sup>\/HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> transporter, NBCn1, was significantly increased. This was followed by a significant increase in CSF secretion rate determined by ventriculo-cisternal perfusion. After five days of treatment with NH<jats:sub>4<\/jats:sub>Cl, CSF [HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup>] levels were normalized. After the normalization of CSF [HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup>], CSF secretion was no longer increased but the abundance of the basolateral Na<jats:sup>+<\/jats:sup>-dependent HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> transporters Ncbe and NBCn1 increased. The luminal HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> transporter, NBCe2, was unaffected by the treatment. In conclusion, we establish that 1) acidotic conditions increase the abundance of the basolateral Na<jats:sup>+<\/jats:sup>-dependent HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> transporters in the choroid plexus, 2) NH<jats:sub>4<\/jats:sub>Cl loading in mice lowers CSF [HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup>] and 3) leads to increased CSF secretion likely caused by the increased capacity for transepithelial transport of Na<jats:sup>+<\/jats:sup> and HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> in the choroid plexus.<\/jats:p>","DOI":"10.3389\/fphys.2024.1491793","type":"journal-article","created":{"date-parts":[[2024,10,21]],"date-time":"2024-10-21T10:29:16Z","timestamp":1729506556000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["NH4Cl-induced metabolic acidosis increases the abundance of HCO3\u2212 transporters in the choroid plexus of mice"],"prefix":"10.3389","volume":"15","author":[{"given":"Laura \u00d8llegaard","family":"Johnsen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed","family":"Sigad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathrine Abildskov","family":"Friis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peder Matzen","family":"Berg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helle Hasager","family":"Damkier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,10,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1007\/s11011-005-2473-2","article-title":"Hyperammonaemia reduces intracellular 22Na (sodium) ion and extracellular 86Rb ion concentrations in the blood-brain barrier of the rat","volume":"20","author":"Alexander","year":"2005","journal-title":"Metab. Brain Dis."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1430","DOI":"10.1172\/JCI117120","article-title":"The fodrin-ankyrin cytoskeleton of choroid plexus preferentially colocalizes with apical Na+K(+)-ATPase rather than with basolateral anion exchanger AE2","volume":"93","author":"Alper","year":"1994","journal-title":"J. Clin. Invest"},{"key":"B3","doi-asserted-by":"publisher","first-page":"516","DOI":"10.1113\/jphysiol.1965.sp007780","article-title":"Effects of Pco2 acetazolamide and ouabain on volume and composition of choroid-plexus fluid","volume":"181","author":"Ames","year":"1965","journal-title":"J. Physiol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1113\/jphysiol.1988.sp016961","article-title":"Concentration of carbon dioxide, interstitial pH and synaptic transmission in hippocampal formation of the rat","volume":"396","author":"Balestrino","year":"1988","journal-title":"J. physiology"},{"key":"B5","article-title":"Spinal puncture and cerebrospinal fluid examination","volume-title":"Roberts and Hedges\u2019 Clinical procedures in emergency medicine and acute care","author":"Bd","year":"2019"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1711","DOI":"10.1681\/ASN.2020010053","article-title":"Impaired renal HCO3 - excretion in cystic fibrosis","volume":"31","author":"Berg","year":"2023","journal-title":"J. Am. Soc. Nephrol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"F68","DOI":"10.1152\/ajprenal.00032.2003","article-title":"Ammonium transport and pH regulation by K(+)-Cl(-) cotransporters","volume":"285","author":"Bergeron","year":"2003","journal-title":"Am. J. physiology. Ren. physiology"},{"key":"B8","doi-asserted-by":"publisher","first-page":"C1448","DOI":"10.1152\/ajpcell.00313.2005","article-title":"Na+-dependent HCO3- uptake into the rat choroid plexus epithelium is partially DIDS sensitive","volume":"289","author":"Bouzinova","year":"2005","journal-title":"Am. J. physiology. Cell physiology"},{"key":"B9","doi-asserted-by":"publisher","first-page":"4709","DOI":"10.1113\/JP275489","article-title":"The choroid plexus sodium-bicarbonate cotransporter NBCe2 regulates mouse cerebrospinal fluid pH","volume":"596","author":"Christensen","year":"2018","journal-title":"J. Physiol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"26998","DOI":"10.1074\/jbc.M110.108712","article-title":"Na+-dependent HCO3- import by the slc4a10 gene product involves Cl- export","volume":"285","author":"Damkier","year":"2010","journal-title":"J. Biol. Chem."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1847","DOI":"10.1152\/physrev.00004.2013","article-title":"Cerebrospinal fluid secretion by the choroid plexus","volume":"93","author":"Damkier","year":"2013","journal-title":"Physiol. Rev."},{"key":"B12","doi-asserted-by":"publisher","first-page":"H172","DOI":"10.1152\/ajpheart.00713.2005","article-title":"An anti-NH2-terminal antibody localizes NBCn1 to heart endothelia and skeletal and vascular smooth muscle cells","volume":"290","author":"Damkier","year":"2006","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"976","DOI":"10.1152\/japplphysiol.00133.2010","article-title":"Central CO2 chemoreception in cardiorespiratory control","volume":"108","author":"Dean","year":"2010","journal-title":"J. Appl. Physiol. (1985)"},{"key":"B14","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1186\/s12987-016-0040-3","article-title":"Fluid and ion transfer across the blood-brain and blood-cerebrospinal fluid barriers; a comparative account of mechanisms and roles","volume":"13","author":"Hladky","year":"2016","journal-title":"Fluids Barriers CNS"},{"key":"B15","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1113\/jphysiol.1977.sp011820","article-title":"Regulation of cerebrospinal fluid bicarbonate by the cat choroid plexus","volume":"267","author":"Husted","year":"1977","journal-title":"J. Physiol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"147ra111","DOI":"10.1126\/scitranslmed.3003748","article-title":"A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid \u03b2","volume":"4","author":"Iliff","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"B17","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1073\/pnas.0705487105","article-title":"Mice with targeted Slc4a10 gene disruption have small brain ventricles and show reduced neuronal excitability","volume":"105","author":"Jacobs","year":"2008","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B18","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1038\/ki.1985.216","article-title":"Monoclonal antibody to Na,K-ATPase: immunocytochemical localization along nephron segments","volume":"28","author":"Kashgarian","year":"1985","journal-title":"Kidney Int."},{"key":"B19","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1152\/jappl.1967.22.2.241","article-title":"Brain CO2 buffering capacity in respiratory acidosis and alkalosis","volume":"22","author":"Kazemi","year":"1967","journal-title":"J. Appl. Physiol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"C1616","DOI":"10.1152\/ajpcell.1994.267.6.C1616","article-title":"Potassium cotransport at the rat choroid plexus","volume":"267","author":"Keep","year":"1994","journal-title":"Am. J. Physiol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1152\/physrev.1972.52.1.1","article-title":"Regulation of cerebrospinal fluid composition with reference to breathing","volume":"52","author":"Leusen","year":"1972","journal-title":"Physiol. Rev."},{"key":"B22","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1016\/0006-8993(84)90250-6","article-title":"Immunohistochemical localization of Na+, K+-ATPase in the choroid plexus","volume":"302","author":"Masuzawa","year":"1984","journal-title":"Brain Res."},{"key":"B23","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1016\/j.bbrc.2008.06.053","article-title":"NBCe2 exhibits a 3 HCO3-:1 Na+ stoichiometry in mouse choroid plexus epithelial cells","volume":"373","author":"Millar","year":"2008","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B24","doi-asserted-by":"publisher","first-page":"2010","DOI":"10.3390\/ijms23042010","article-title":"Severe acute hepatic dysfunction induced by ammonium acetate treatment results in choroid plexus swelling and ventricle enlargement in the brain","volume":"23","author":"Nakadate","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"B25","doi-asserted-by":"publisher","first-page":"7275","DOI":"10.1073\/pnas.90.15.7275","article-title":"Distribution of the aquaporin CHIP in secretory and resorptive epithelia and capillary endothelia","volume":"90","author":"Nielsen","year":"1993","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B26","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1113\/jphysiol.2003.046474","article-title":"Basolateral Na+-dependent HCO3- transporter NBCn1-mediated HCO3- influx in rat medullary thick ascending limb","volume":"555","author":"Odgaard","year":"2004","journal-title":"J. Physiol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"852","DOI":"10.1681\/asn.2019060613","article-title":"NBCn1 increases NH(4) (+) reabsorption across thick ascending limbs, the capacity for urinary NH(4) (+) excretion, and early recovery from metabolic acidosis","volume":"32","author":"Olsen","year":"2021","journal-title":"J. Am. Soc. Nephrol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1096\/fj.04-1711fje","article-title":"Reduced cerebrospinal fluid production and intracranial pressure in mice lacking choroid plexus water channel Aquaporin-1","volume":"19","author":"Oshio","year":"2005","journal-title":"FASEB J."},{"key":"B29","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1152\/ajplegacy.1965.208.3.436","article-title":"Role of cerebral fluids in control of respiration as studied in unanesthetized goats","volume":"208","author":"Pappenheimer","year":"1965","journal-title":"Am. J. physiology"},{"key":"B30","doi-asserted-by":"publisher","first-page":"12777","DOI":"10.1074\/jbc.M707829200","article-title":"Characterization of human SLC4A10 as an electroneutral Na\/HCO3 cotransporter (NBCn2) with Cl-self-exchange activity","volume":"283","author":"Parker","year":"2008","journal-title":"J. Biol. Chem."},{"key":"B31","doi-asserted-by":"publisher","first-page":"C173","DOI":"10.1152\/ajpcell.1997.272.1.C173","article-title":"Expression of the Na+-K+-2Cl- cotransporter BSC2 in the nervous system","volume":"272","author":"Plotkin","year":"1997","journal-title":"Am. J. Physiol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"C601","DOI":"10.1152\/ajpcell.00240.2003","article-title":"A SCL4A10 gene product maps selectively to the basolateral plasma membrane of choroid plexus epithelial cells","volume":"286","author":"Praetorius","year":"2004","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"e20190062","DOI":"10.1084\/jem.20190062","article-title":"The blood-brain barrier in health and disease: important unanswered questions","volume":"217","author":"Profaci","year":"2020","journal-title":"J. Exp. Med."},{"key":"B34","doi-asserted-by":"publisher","first-page":"817","DOI":"10.1038\/nm1422","article-title":"Experimental febrile seizures are precipitated by a hyperthermia-induced respiratory alkalosis","volume":"12","author":"Schuchmann","year":"2006","journal-title":"Nat. Med."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1309","DOI":"10.1177\/32.12.6094658","article-title":"Purification of mouse brain (Na+ + K+)-ATPase catalytic unit, characterization of antiserum, and immunocytochemical localization in cerebellum, choroid plexus, and kidney","volume":"32","author":"Siegel","year":"1984","journal-title":"J. Histochem Cytochem"},{"key":"B36","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1038\/ki.1972.47","article-title":"Symposium on acid-base homeostasis. The regulation of cerebrospinal fluid pH","volume":"1","author":"Siesjo","year":"1972","journal-title":"Kidney Int."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1267","DOI":"10.1007\/s00424-017-1997-8","article-title":"Measurement of total CO2 in microliter samples of urine and other biological fluids using infrared detection of CO2","volume":"469","author":"Trepiccione","year":"2017","journal-title":"Pflugers Arch."},{"key":"B38","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1016\/0006-8993(81)91071-4","article-title":"The effect of furosemide and bumetanide on cerebrospinal fluid formation","volume":"221","author":"Vogh","year":"1981","journal-title":"Brain Res."},{"key":"B39","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1111\/j.1469-185X.1954.tb00597.x","article-title":"The perivascular spaces of the mammalian central nervous system and their relation to the perineuronal and subarachnoid spaces","volume":"89","author":"Woollam","year":"1955","journal-title":"J. Anat."}],"container-title":["Frontiers in Physiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2024.1491793\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,21]],"date-time":"2024-10-21T10:29:20Z","timestamp":1729506560000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2024.1491793\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,21]]},"references-count":39,"alternative-id":["10.3389\/fphys.2024.1491793"],"URL":"https:\/\/doi.org\/10.3389\/fphys.2024.1491793","relation":{},"ISSN":["1664-042X"],"issn-type":[{"value":"1664-042X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,21]]},"article-number":"1491793"}}