title: Potassium Sensing by Renal Distal Tubules Requires Kir4.1.
abstract: The mammalian distal convoluted tubule (DCT) makes an important contribution to potassium homeostasis by modulating NaCl transport. The thiazide-sensitive Na+/Cl-cotransporter (NCC) is activated by low potassium intake and by hypokalemia. Coupled with suppression of aldosterone secretion, activation of NCC helps to retain potassium by increasing electroneutral NaCl reabsorption, therefore reducing Na+/K+exchange. Yet the mechanisms by which DCT cells sense plasma potassium concentration and transmit the information to the apical membrane are not clear. Here, we tested the hypothesis that the potassium channel Kir4.1 is the potassium sensor of DCT cells. We generated mice in which Kir4.1 could be deleted in the kidney after the mice are fully developed. Deletion of Kir4.1 in these mice led to moderate salt wasting, low BP, and profound potassium wasting. Basolateral membranes of DCT cells were depolarized, nearly devoid of conductive potassium transport, and unresponsive to plasma potassium concentration. Although renal WNK4 abundance increased after Kir4.1 deletion, NCC abundance and function decreased, suggesting that membrane depolarization uncouples WNK kinases from NCC. Together, these results indicate that Kir4.1 mediates potassium sensing by DCT cells and couples this signal to apical transport processes.
authors.affiliation: Division of Nephrology and Hypertension, Departments of Medicine and Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon.
authors.forename: Catherina A
authors.initials: CA
authors.lastname: Cuevas
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York; and.
authors.forename: Xiao-Tong
authors.initials: XT
authors.lastname: Su
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York; and.
authors.forename: Ming-Xiao
authors.initials: MX
authors.lastname: Wang
authors.affiliation: Division of Nephrology and Hypertension, Departments of Medicine and Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Terker
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York; and.
authors.forename: Dao-Hong
authors.initials: DH
authors.lastname: Lin
authors.affiliation: Division of Nephrology and Hypertension, Departments of Medicine and Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon.
authors.forename: James A
authors.initials: JA
authors.lastname: McCormick
authors.affiliation: Division of Nephrology and Hypertension, Departments of Medicine and Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon.|Renal Section, Veterans Administration Portland Health Care System, Portland, Oregon.
authors.forename: Chao-Ling
authors.initials: CL
authors.lastname: Yang
authors.affiliation: Division of Nephrology and Hypertension, Departments of Medicine and Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon; Ellisond@ohsu.edu Wenhui_wang@nymc.edu.|Renal Section, Veterans Administration Portland Health Care System, Portland, Oregon.
authors.forename: David H
authors.initials: DH
authors.lastname: Ellison
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York; and Ellisond@ohsu.edu Wenhui_wang@nymc.edu.
authors.forename: Wen-Hui
authors.initials: WH
authors.lastname: Wang
mesh_terms: D000818:Animals; D007686:Kidney Tubules, Distal / Q000166:cytology / Q000502:physiology*; D051379:Mice; D011188:Potassium; D024661:Potassium Channels, Inwardly Rectifying / Q000502:physiology*; D000098854:Kcnj10 Channel
chemical_list: D000098854:Kcnj10 Channel; D024661:Potassium Channels, Inwardly Rectifying; D011188:Potassium
keywords: diuretics; potassium channels; slc12a3; spak; thiazide; wnk4