title: Renal defects in KCNE1 knockout mice are mimicked by chromanol 293B in vivo: identification of a KCNE1-regulated K+ conductance in the proximal tubule.
abstract: KCNE1 is a protein of low molecular mass that is known to regulate the chromanol 293B and clofilium-sensitive K+ channel, KCNQ1, in a number of tissues. Previous work on the kidney of KCNE1 and KCNQ1 knockout mice has revealed that these animals have different renal phenotypes, suggesting that KCNE1 may not regulate KCNQ1 in the renal system. In the current study, in vivo clearance approaches and whole cell voltage-clamp recordings from isolated renal proximal tubules were used to examine the physiological role of KCNE1. Data from wild-type mice were compared to those from KCNE1 knockout mice. In clearance studies the KCNE1 knockout mice had an increased fractional excretion of Na+, Cl−, HCO3(−) and water. This profile was mimicked in wild-type mice by infusion of chromanol 293B, while chromanol was without effect in KCNE1 knockout animals. Clofilium also increased the fractional excretion of Na+, Cl− and water, but this was observed in both wild-type and knockout mice, suggesting that KCNE1 was regulating a chromanol-sensitive but clofilium-insensitive pathway. In whole cell voltage clamp recordings from proximal tubules, a chromanol-sensitive, K+-selective conductance was identified that was absent in tubules from knockout animals. The properties of this conductance were not consistent with its being mediated by KCNQ1, suggesting that KCNE1 regulates another K+ channel in the renal proximal tubule. Taken together these data suggest that KCNE1 regulates a K+-selective conductance in the renal proximal tubule that plays a relatively minor role in driving the transport of Na+, Cl− and HCO3(−).
authors.affiliation: Department of Biomedical Science, University of Sheffield, Sheffield S10 2TN, UK.
authors.forename: A M
authors.initials: AM
authors.lastname: Neal
authors.forename: H C
authors.initials: HC
authors.lastname: Taylor
authors.forename: I D
authors.initials: ID
authors.lastname: Millar
authors.forename: J D
authors.initials: JD
authors.lastname: Kibble
authors.forename: S J
authors.initials: SJ
authors.lastname: White
authors.forename: L
authors.initials: L
authors.lastname: Robson
mesh_terms: D000818:Animals; D001464:Barium / Q000494:pharmacology; D001639:Bicarbonates / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D002839:Chromans / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D017136:Ion Transport / Q000187:drug effects / Q000502:physiology; D051657:KCNQ1 Potassium Channel / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D011188:Potassium / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D012964:Sodium / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D001639:Bicarbonates; D002712:Chlorides; D002839:Chromans; D051657:KCNQ1 Potassium Channel; C092068:Kcne1 protein, mouse; D024642:Potassium Channels, Voltage-Gated; D000644:Quaternary Ammonium Compounds; D013449:Sulfonamides; C103474:6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethylchromane; D001464:Barium; C022799:clofilium; D012964:Sodium; D005947:Glucose; D011188:Potassium