Renal phenotype in mice lacking the Kir5.1 (Kcnj16) K+channel subunit contrasts with that observed in SeSAME/EAST syndrome

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 25; pp. 10361 - 10366
• Main Authors: Paulais, Marc, Bloch-Faure, May, Picard, Nicolas, Jacques, Thibaut, Ramakrishnan, Suresh Krishna, Keck, Mathilde, Sohet, Fabien, Eladari, Dominique, Houillier, Pascal, Lourdel, Stéphane, Teulon, Jacques, Tucker, Stephen J.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences Issue 21.06.2011; National Acad Sciences; National Academy of Sciences
• Subjects: Acidosis; Acidosis - genetics; Acidosis - physiopathology; Amiloride - pharmacology; Animals; Ataxia; Biochemistry, Molecular Biology; Biological Sciences; Deafness; Diuretics - pharmacology; Excretion; Furosemide - pharmacology; Genetic mutation; Genetics; Genotype & phenotype; Human health and pathology; Humans; Hydrochlorothiazide - pharmacology; Hypercalciuria; Hypokalemia - genetics; Hypokalemia - physiopathology; Kidney Tubules - cytology; Kidney Tubules - drug effects; Kidney Tubules - physiology; Kidney Tubules - physiopathology; Kidneys; Kir5.1 Channel; Life Sciences; Membranes; Mice; Mice, Knockout; Molecular biology; Mutation; Nephrology; Nephrons; Patch-Clamp Techniques; Phenotype; Phenotypes; Potassium Channels, Inwardly Rectifying - genetics; Potassium Channels, Inwardly Rectifying - metabolism; Rodents; Sodium Channel Blockers - pharmacology; Sodium Potassium Chloride Symporter Inhibitors - pharmacology; Syndrome; Urine; Urology and Nephrology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1101400108

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.