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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.

Original publication

DOI

10.1073/pnas.1101400108

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

21/06/2011

Volume

108

Pages

10361 - 10366

Keywords

Acidosis, Amiloride, Animals, Diuretics, Furosemide, Humans, Hydrochlorothiazide, Hypokalemia, Kidney Tubules, Mice, Mice, Knockout, Patch-Clamp Techniques, Phenotype, Potassium Channels, Inwardly Rectifying, Sodium Channel Blockers, Sodium Potassium Chloride Symporter Inhibitors, Syndrome