title: ENaC and ROMK activity are inhibited in the DCT2/CNT of TgWnk4PHAIImice.
abstract: Mice transgenic for genomic segments harboring PHAII (pseudohypoaldosteronism type II) mutant Wnk4 (with-No-Lysine kinase 4) (TgWnk4PHAII) have hyperkalemia which is currently believed to be the result of high activity of Na-Cl cotransporter (NCC). This leads to decreasing Na+delivery to the distal nephron segment including late distal convoluted tubule (DCT) and connecting tubule (CNT). Since epithelial Na+channel (ENaC) and renal outer medullary K+channel (ROMK or Kir4.1) are expressed in the late DCT and play an important role in mediating K+secretion, the aim of the present study is to test whether ROMK and ENaC activity in the DCT/CNT are also compromised in the mice expressing PHAII mutant Wnk4. Western blot analysis shows that the expression of βENaC and γENaC subunits but not αENaC subunit was lower in TgWnk4PHAIImice than that in wild-type (WT) and TgWnk4WTmice. Patch-clamp experiments detected amiloride-sensitive Na+currents and TPNQ-sensitive K+currents in DCT2/CNT, suggesting the activity of ENaC and ROMK. However, both Na+and ROMK currents in DCT2/CNT of TgWnk4PHAIImice were significantly smaller than those in WT and TgWnk4WTmice. In contrast, the basolateral K+currents in the DCT were similar among three groups, despite higher NCC expression in TgWnk4PHAIImice than those of WT and TgWnk4WTmice. An increase in dietary K+intake significantly increased both ENaC and ROMK currents in the DCT2/CNT of all three groups. However, high-K+(HK) intake-induced stimulation of Na+and K+currents was smaller in TgWnk4PHAIImice than those in WT and TgWnk4WTmice. We conclude that ENaC and ROMK channel activity in DCT2/CNT are inhibited in TgWnk4PHAIImice and that Wnk4PHAII-induced inhibition of ENaC and ROMK may contribute to the suppression of K+secretion in the DCT2/CNT in addition to increased NCC activity.
authors.affiliation: Department of Physiology, Xuzhou Medical University, Xuzhou, Jiangsu, China.|Department of Pharmacology, New York Medical College, Valhalla, New York.
authors.forename: Chengbiao
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York.|Department of Physiology, Harbin Medical University, Harbin, China; and.
authors.forename: Lijun
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York.
authors.forename: Xiao-Tong
authors.initials: XT
authors.lastname: Su
authors.affiliation: Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Junhui
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York.
authors.forename: Dao-Hong
authors.initials: DH
authors.lastname: Lin
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York; Wenhui_wang@nymc.edu.
authors.forename: Wen-Hui
authors.initials: WH
authors.lastname: Wang
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation; D053503:Epithelial Sodium Channels / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020022:Genetic Predisposition to Disease; D006947:Hyperkalemia / Q000235:genetics / Q000378:metabolism; D007686:Kidney Tubules, Distal / Q000378:metabolism*; D056929:Liddle Syndrome / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D011188:Potassium / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism*; D017419:Potassium, Dietary / Q000008:administration & dosage / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D065667:Renal Elimination; D015398:Signal Transduction
chemical_list: D053503:Epithelial Sodium Channels; C510693:Kcnj1 protein, mouse; D024661:Potassium Channels, Inwardly Rectifying; D017419:Potassium, Dietary; C507049:Scnn1b protein, mouse; C507053:Scnn1g protein, mouse; C499024:Prkwnk4 protein, mouse; D017346:Protein Serine-Threonine Kinases; D011188:Potassium
keywords: K secretion; Kir1.1; Kir4.1; hyperkalemia; pseudohypoaldosteronism type II