Double Knockout of the Na + -Driven Cl − /HCO 3 − Exchanger and Na + /Cl − Cotransporter Induces Hypokalemia and Volume Depletion

Autor: Régine Chambrey, Christian A. Hübner, Anne Sinning, Maximilien Jayat, Karen I. López-Cayuqueo, Stéphanie Baron, R. Todd Alexander, Nicolas Cornière, Juliette Hadchouel, Dominique Eladari, Nikita Radionov, Francesco Trepiccione
Přispěvatelé: Friedrich-Schiller-Universität = Friedrich Schiller University Jena [Jena, Germany], Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Centro de Estudios Científicos (CECs), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), University of Alberta, Centre National de la Recherche Scientifique (CNRS), Hadchouel, Juliette, Sinning, Anne, Radionov, Nikita, Trepiccione, Francesco, López Cayuqueo, Karen I, Jayat, Maximilien, Baron, Stéphanie, Cornière, Nicola, Alexander, R. Todd, Eladari, Dominique, Hübner, Christian A, Chambrey, Régine
Jazyk: angličtina
Rok vydání: 2017
Předmět:
0301 basic medicine
Epithelial sodium channel
medicine.medical_specialty
hypertension
[SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO]
diuretic
030232 urology & nephrology
Mice
03 medical and health sciences
0302 clinical medicine
Downregulation and upregulation
[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
In vivo
Internal medicine
medicine
hypokalemia
[SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO]
Animals
Chloride-Bicarbonate Antiporters
Thiazide
Mice
Knockout
Blood Volume
biology
Animal
Chemistry
Chloride-Bicarbonate Antiporter
General Medicine
Pendrin
Hypokalemia
diuretics
Up-Regulation
[SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
Basic Research
030104 developmental biology
Endocrinology
Nephrology
biology.protein
medicine.symptom
Cotransporter
Homeostasis
medicine.drug
Zdroj: Journal of the American Society of Nephrology
Journal of the American Society of Nephrology, 2017, 28 (1), pp.130-139. ⟨10.1681/ASN.2015070734⟩
ISSN: 1046-6673
1533-3450
Popis: International audience; 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.
Databáze: OpenAIRE
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