title: Double Knockout of the Na+-Driven Cl-/HCO3- Exchanger and Na+/Cl- Cotransporter Induces Hypokalemia and Volume Depletion.
abstract: We recently described a novel thiazide-sensitive electroneutral NaCl transport mechanism resulting from the parallel operation of the Cl-/HCO3-exchanger pendrin and the Na+-driven Cl-/2HCO3-exchanger (NDCBE) in β-intercalated cells of the collecting duct. Although a role for pendrin in maintaining Na+balance, intravascular volume, and BP is well supported, there is no in vivo evidence for the role of NDCBE in maintaining Na+balance. Here, we show that deletion of NDCBE in mice caused only subtle perturbations of Na+homeostasis and provide evidence that the Na+/Cl-cotransporter (NCC) compensated for the inactivation of NDCBE. To unmask the role of NDCBE, we generated Ndcbe/Ncc double-knockout (dKO) mice. On a normal salt diet, dKO and single-knockout mice exhibited similar activation of the renin-angiotensin-aldosterone system, whereas only dKO mice displayed a lower blood K+concentration. Furthermore, dKO mice displayed upregulation of the epithelial sodium channel (ENaC) and the Ca2+-activated K+channel BKCa. During NaCl depletion, only dKO mice developed marked intravascular volume contraction, despite dramatically increased renin activity. Notably, the increase in aldosterone levels expected on NaCl depletion was attenuated in dKO mice, and single-knockout and dKO mice had similar blood K+concentrations under this condition. In conclusion, NDCBE is necessary for maintaining sodium balance and intravascular volume during salt depletion or NCC inactivation in mice. Furthermore, NDCBE has an important role in the prevention of hypokalemia. Because NCC and NDCBE are both thiazide targets, the combined inhibition of NCC and the NDCBE/pendrin system may explain thiazide-induced hypokalemia in some patients.
authors.affiliation: Institut für Humangenetik, University Hospital Jena, Friedrich Schiller Universität, Jena, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Sinning
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U970, Paris Cardiovascular Research Center, Paris, France.|Faculty de Medicine, Université Paris-Descartes, Paris, France.
authors.forename: Nikita
authors.initials: N
authors.lastname: Radionov
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U970, Paris Cardiovascular Research Center, Paris, France.|Faculty de Medicine, Université Paris-Descartes, Paris, France.
authors.forename: Francesco
authors.initials: F
authors.lastname: Trepiccione
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U970, Paris Cardiovascular Research Center, Paris, France.|Centro de Estudios Científicos (CECs), Valdivia, Chile.|Faculty de Medicine, Université Paris-Descartes, Paris, France.
authors.forename: Karen I
authors.initials: KI
authors.lastname: López-Cayuqueo
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U970, Paris Cardiovascular Research Center, Paris, France.|Faculty de Medicine, Université Paris-Descartes, Paris, France.
authors.forename: Maximilien
authors.initials: M
authors.lastname: Jayat
authors.affiliation: Department de Physiologie, Hopital Européen Georges Pompidou, Assistance Publique-Hopitaux de Paris, Paris, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Baron
authors.affiliation: Service de Néphrologie et Transplantation Rénale, Centre Hospitalier Universitaire de La Réunion, St. Denis, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Cornière
authors.affiliation: Departments of Pediatrics and Physiology, University of Alberta, Edmonton, Alberta, Canada; and.
authors.forename: R Todd
authors.initials: RT
authors.lastname: Alexander
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U970, Paris Cardiovascular Research Center, Paris, France.|Faculty de Medicine, Université Paris-Descartes, Paris, France.
authors.forename: Juliette
authors.initials: J
authors.lastname: Hadchouel
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U970, Paris Cardiovascular Research Center, Paris, France.|Faculty de Medicine, Université Paris-Descartes, Paris, France.|Department de Physiologie, Hopital Européen Georges Pompidou, Assistance Publique-Hopitaux de Paris, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Eladari
authors.affiliation: Institut für Humangenetik, University Hospital Jena, Friedrich Schiller Universität, Jena, Germany.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Hübner
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U970, Paris Cardiovascular Research Center, Paris, France; regine.chambrey@inserm.fr.|Faculty de Medicine, Université Paris-Descartes, Paris, France.|Centre National de la Recherche Scientifique, Paris, France.
authors.forename: Régine
authors.initials: R
authors.lastname: Chambrey
mesh_terms: D000818:Animals; D001810:Blood Volume; D027963:Chloride-Bicarbonate Antiporters / Q000502:physiology*; D007008:Hypokalemia / Q000209:etiology*; D051379:Mice; D018345:Mice, Knockout; D015854:Up-Regulation
chemical_list: D027963:Chloride-Bicarbonate Antiporters
keywords: diuretics; hypertension; hypokalemia