AUTHOR=Johnsen Laura Øllegaard , Sigad Ahmed , Friis Kathrine Abildskov , Berg Peder Matzen , Damkier Helle Hasager TITLE=NH4Cl-induced metabolic acidosis increases the abundance of HCO3− transporters in the choroid plexus of mice JOURNAL=Frontiers in Physiology VOLUME=15 YEAR=2024 URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2024.1491793 DOI=10.3389/fphys.2024.1491793 ISSN=1664-042X ABSTRACT=

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 HCO₃⁻ across the choroid plexus in the brain ventricles. Acute regulation in response to acidosis is dependent on H⁺ export and HCO₃⁻ import across the plasma membrane. Acute regulation in response to alkalosis is dependent on HCO₃⁻ export across the plasma membrane. The objective of the study was to investigate the contribution of the Na⁺-dependent HCO₃⁻ 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 (NH₄Cl) in the drinking water for three, five, or seven days. While in vivo, CSF pH measurements did not differ, measurements of CSF [HCO₃⁻] revealed a significantly lower CSF [HCO₃⁻] after three days of acid-loading. Immunoblotting of choroid plexus protein samples showed that the abundance of the basolateral Na⁺/HCO₃⁻ 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 NH₄Cl, CSF [HCO₃⁻] levels were normalized. After the normalization of CSF [HCO₃⁻], CSF secretion was no longer increased but the abundance of the basolateral Na⁺-dependent HCO₃⁻ transporters Ncbe and NBCn1 increased. The luminal HCO₃⁻ transporter, NBCe2, was unaffected by the treatment. In conclusion, we establish that 1) acidotic conditions increase the abundance of the basolateral Na⁺-dependent HCO₃⁻ transporters in the choroid plexus, 2) NH₄Cl loading in mice lowers CSF [HCO₃⁻] and 3) leads to increased CSF secretion likely caused by the increased capacity for transepithelial transport of Na⁺ and HCO₃⁻ in the choroid plexus.