title: Hypokalemia and Pendrin Induction by Aldosterone.
abstract: Aldosterone plays an important role in regulating Na-Cl reabsorption and blood pressure. Epithelial Na+channel, Na+-Cl-cotransporter, and Cl-/HCO3-exchanger pendrin are the major mediators of Na-Cl transport in the aldosterone-sensitive distal nephron. Existing evidence also suggests that plasma K+concentration affects renal Na-Cl handling. In this study, we posited that hypokalemia modulates the effects of aldosterone on pendrin in hyperaldosteronism. Chronic aldosterone infusion in mice increased pendrin levels at the plasma membrane, and correcting hypokalemia in this model almost completely blocked pendrin upregulation. However, hypokalemia induced by a low-K+diet resulted in pendrin downregulation along with reduced plasma aldosterone levels, indicating that both hypokalemia and aldosterone excess are necessary for pendrin induction. In contrast, decreased plasma K+levels were sufficient to increase Na+-Cl-cotransporter levels. We found that phosphorylation of mineralocorticoid receptor that prevents aldosterone binding in intercalated cells was suppressed by hypokalemia, which resulted in enhanced pendrin response to aldosterone, explaining the coordinated action of aldosterone and hypokalemia in pendrin regulation. Finally, to address the physiological significance of our observations, we administered aldosterone to mice lacking pendrin. Notably, plasma K+levels were significantly lower in pendrin knockout mice (2.7±0.1 mmol/L) than in wild-type mice (3.0±0.1 mmol/L) after aldosterone infusion, demonstrating that pendrin alleviates hypokalemia in a state of aldosterone excess. These data indicate that the decreased plasma K+levels promote pendrin induction by aldosterone, which, in concert with Na+-Cl-cotransporter, counteracts the progression of hypokalemia but promotes hypertension in primary aldosterone excess.
authors.affiliation: From the Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan (N.X., K.I., S.U., S.S.); Department of Nephrology, Tianjin First Central Hospital, China (N.X., W.X.C.); and Division of Clinical Epigenetics, Research Center for Advanced Science and Technology (D.H., T.F., S.S.) and Department of Clinical Laboratory, School of Medicine (T.S.), The University of Tokyo, Japan.
authors.forename: Ning
authors.initials: N
authors.lastname: Xu
authors.affiliation: From the Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan (N.X., K.I., S.U., S.S.); Department of Nephrology, Tianjin First Central Hospital, China (N.X., W.X.C.); and Division of Clinical Epigenetics, Research Center for Advanced Science and Technology (D.H., T.F., S.S.) and Department of Clinical Laboratory, School of Medicine (T.S.), The University of Tokyo, Japan.
authors.forename: Daigoro
authors.initials: D
authors.lastname: Hirohama
authors.affiliation: From the Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan (N.X., K.I., S.U., S.S.); Department of Nephrology, Tianjin First Central Hospital, China (N.X., W.X.C.); and Division of Clinical Epigenetics, Research Center for Advanced Science and Technology (D.H., T.F., S.S.) and Department of Clinical Laboratory, School of Medicine (T.S.), The University of Tokyo, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Ishizawa
authors.affiliation: From the Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan (N.X., K.I., S.U., S.S.); Department of Nephrology, Tianjin First Central Hospital, China (N.X., W.X.C.); and Division of Clinical Epigenetics, Research Center for Advanced Science and Technology (D.H., T.F., S.S.) and Department of Clinical Laboratory, School of Medicine (T.S.), The University of Tokyo, Japan.
authors.forename: Wen Xiu
authors.initials: WX
authors.lastname: Chang
authors.affiliation: From the Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan (N.X., K.I., S.U., S.S.); Department of Nephrology, Tianjin First Central Hospital, China (N.X., W.X.C.); and Division of Clinical Epigenetics, Research Center for Advanced Science and Technology (D.H., T.F., S.S.) and Department of Clinical Laboratory, School of Medicine (T.S.), The University of Tokyo, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Shimosawa
authors.affiliation: From the Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan (N.X., K.I., S.U., S.S.); Department of Nephrology, Tianjin First Central Hospital, China (N.X., W.X.C.); and Division of Clinical Epigenetics, Research Center for Advanced Science and Technology (D.H., T.F., S.S.) and Department of Clinical Laboratory, School of Medicine (T.S.), The University of Tokyo, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Fujita
authors.affiliation: From the Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan (N.X., K.I., S.U., S.S.); Department of Nephrology, Tianjin First Central Hospital, China (N.X., W.X.C.); and Division of Clinical Epigenetics, Research Center for Advanced Science and Technology (D.H., T.F., S.S.) and Department of Clinical Laboratory, School of Medicine (T.S.), The University of Tokyo, Japan.
authors.forename: Shunya
authors.initials: S
authors.lastname: Uchida
authors.affiliation: From the Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan (N.X., K.I., S.U., S.S.); Department of Nephrology, Tianjin First Central Hospital, China (N.X., W.X.C.); and Division of Clinical Epigenetics, Research Center for Advanced Science and Technology (D.H., T.F., S.S.) and Department of Clinical Laboratory, School of Medicine (T.S.), The University of Tokyo, Japan. shigeru.shibata@med.teikyo-u.ac.jp.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Shibata
mesh_terms: D000450:Aldosterone / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D027321:Anion Transport Proteins / Q000235:genetics / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004032:Diet; D015536:Down-Regulation / Q000187:drug effects; D006973:Hypertension / Q000378:metabolism; D007008:Hypokalemia / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D049992:Sodium Chloride Symporters / Q000235:genetics / Q000378:metabolism; D000076988:Sulfate Transporters; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D027321:Anion Transport Proteins; D018161:Receptors, Mineralocorticoid; C494849:Slc26a4 protein, mouse; D049992:Sodium Chloride Symporters; D000076988:Sulfate Transporters; D000450:Aldosterone
keywords: aldosterone; blood pressure; hypertension; hypokalemia; potassium