title: Renal phenotype in mice lacking the Kir5.1 (Kcnj16) K+ channel subunit contrasts with that observed in SeSAME/EAST syndrome.
abstract: The heteromeric inwardly rectifying Kir4.1/Kir5.1 K(+) channel underlies the basolateral K(+) conductance in the distal nephron and is extremely sensitive to inhibition by intracellular pH. The functional importance of Kir4.1/Kir5.1 in renal ion transport has recently been highlighted by mutations in the human Kir4.1 gene (KCNJ10) that result in seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME)/epilepsy, ataxia, sensorineural deafness, and renal tubulopathy (EAST) syndrome, a complex disorder that includes salt wasting and hypokalemic alkalosis. Here, we investigated the role of the Kir5.1 subunit in mice with a targeted disruption of the Kir5.1 gene (Kcnj16). The Kir5.1(-/-) mice displayed hypokalemic, hyperchloremic metabolic acidosis with hypercalciuria. The short-term responses to hydrochlorothiazide, an inhibitor of ion transport in the distal convoluted tubule (DCT), were also exaggerated, indicating excessive renal Na(+) absorption in this segment. Furthermore, chronic treatment with hydrochlorothiazide normalized urinary excretion of Na(+) and Ca(2+), and abolished acidosis in Kir5.1(-/-) mice. Finally, in contrast to WT mice, electrophysiological recording of K(+) channels in the DCT basolateral membrane of Kir5.1(-/-) mice revealed that, even though Kir5.1 is absent, there is an increased K(+) conductance caused by the decreased pH sensitivity of the remaining homomeric Kir4.1 channels. In conclusion, disruption of Kcnj16 induces a severe renal phenotype that, apart from hypokalemia, is the opposite of the phenotype seen in SeSAME/EAST syndrome. These results highlight the important role that Kir5.1 plays as a pH-sensitive regulator of salt transport in the DCT, and the implication of these results for the correct genetic diagnosis of renal tubulopathies is discussed.
authors.affiliation: Université Pierre et Marie Curie Paris 6, Université Paris 5, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche en Santé 872, 75006 Paris, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Paulais
authors.forename: May
authors.initials: M
authors.lastname: Bloch-Faure
authors.forename: Nicolas
authors.initials: N
authors.lastname: Picard
authors.forename: Thibaut
authors.initials: T
authors.lastname: Jacques
authors.forename: Suresh Krishna
authors.initials: SK
authors.lastname: Ramakrishnan
authors.forename: Mathilde
authors.initials: M
authors.lastname: Keck
authors.forename: Fabien
authors.initials: F
authors.lastname: Sohet
authors.forename: Dominique
authors.initials: D
authors.lastname: Eladari
authors.forename: Pascal
authors.initials: P
authors.lastname: Houillier
authors.forename: Stéphane
authors.initials: S
authors.lastname: Lourdel
authors.forename: Jacques
authors.initials: J
authors.lastname: Teulon
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Tucker
mesh_terms: D000138:Acidosis / Q000235:genetics / Q000503:physiopathology; D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D004232:Diuretics / Q000494:pharmacology; D005665:Furosemide / Q000494:pharmacology; D006801:Humans; D006852:Hydrochlorothiazide / Q000494:pharmacology; D007008:Hypokalemia / Q000235:genetics / Q000503:physiopathology; D007684:Kidney Tubules / Q000166:cytology / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D010641:Phenotype; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000494:pharmacology; D013577:Syndrome; D000097062:Kir5.1 Channel
chemical_list: D000584:Amiloride; D004232:Diuretics; D005665:Furosemide; D006852:Hydrochlorothiazide; D024661:Potassium Channels, Inwardly Rectifying; D026941:Sodium Channel Blockers; D049994:Sodium Potassium Chloride Symporter Inhibitors; D000097062:Kir5.1 Channel