title: KCNJ10 determines the expression of the apical Na-Cl cotransporter (NCC) in the early distal convoluted tubule (DCT1).
abstract: The renal phenotype induced by loss-of-function mutations of inwardly rectifying potassium channel (Kir), Kcnj10 (Kir4.1), includes salt wasting, hypomagnesemia, metabolic alkalosis and hypokalemia. However, the mechanism by which Kir.4.1 mutations cause the tubulopathy is not completely understood. Here we demonstrate that Kcnj10 is a main contributor to the basolateral K conductance in the early distal convoluted tubule (DCT1) and determines the expression of the apical Na-Cl cotransporter (NCC) in the DCT. Immunostaining demonstrated Kcnj10 and Kcnj16 were expressed in the basolateral membrane of DCT, and patch-clamp studies detected a 40-pS K channel in the basolateral membrane of the DCT1 of p8/p10 wild-type Kcnj10(+/+) mice (WT). This 40-pS K channel is absent in homozygous Kcnj10(-/-) (knockout) mice. The disruption of Kcnj10 almost completely eliminated the basolateral K conductance and decreased the negativity of the cell membrane potential in DCT1. Moreover, the lack of Kcnj10 decreased the basolateral Cl conductance, inhibited the expression of Ste20-related proline-alanine-rich kinase and diminished the apical NCC expression in DCT. We conclude that Kcnj10 plays a dominant role in determining the basolateral K conductance and membrane potential of DCT1 and that the basolateral K channel activity in the DCT determines the apical NCC expression possibly through a Ste20-related proline-alanine-rich kinase-dependent mechanism.
authors: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou 221002, China;Department of Pharmacology, New York Medical College, Valhalla, NY 10595; and.
authors: Chengbiao
authors: C
authors: Zhang
authors: Department of Pharmacology, New York Medical College, Valhalla, NY 10595; and.
authors: Lijun
authors: L
authors: Wang
authors: Department of Genetics, Howard Hughes Medical Institute, and.
authors: Junhui
authors: J
authors: Zhang
authors: Department of Pharmacology, New York Medical College, Valhalla, NY 10595; and.
authors: Xiao-Tong
authors: XT
authors: Su
authors: Department of Pharmacology, New York Medical College, Valhalla, NY 10595; and.
authors: Dao-Hong
authors: DH
authors: Lin
authors: Department of Genetics, Howard Hughes Medical Institute, and.
authors: Ute I
authors: UI
authors: Scholl
authors: Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510 wenhui_wang@nymc.edu gerhard.giebisch@yale.edu.
authors: Gerhard
authors: G
authors: Giebisch
authors: Department of Genetics, Howard Hughes Medical Institute, and.
authors: Richard P
authors: RP
authors: Lifton
authors: Department of Pharmacology, New York Medical College, Valhalla, NY 10595; and wenhui_wang@nymc.edu gerhard.giebisch@yale.edu.
authors: Wen-Hui
authors: WH
authors: Wang
mesh_terms: D000818:Animals; D007150:Immunohistochemistry; D007686:Kidney Tubules, Distal / Q000378:metabolism*; D008564:Membrane Potentials; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D018408:Patch-Clamp Techniques; D024661:Potassium Channels, Inwardly Rectifying / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D064486:Solute Carrier Family 12, Member 3 / Q000378:metabolism; D000097062:Kir5.1 Channel; D000098854:Kcnj10 Channel
chemical_list: D024661:Potassium Channels, Inwardly Rectifying; D064486:Solute Carrier Family 12, Member 3; D000097062:Kir5.1 Channel; D000098854:Kcnj10 Channel; C578875:Slc12a3 protein, mouse
keywords: Kir.5.1; SPAK; SeSAME/EAST syndrome; WNK