The autosomal recessive EAST/SeSAME syndrome is caused by loss-of-function mutations of KCNJ10 (Kir4.1), a basolateral potassium channel of distal convoluted and connecting tubules. EAST patients suffer from epilepsy, ataxia, sensorineural deafness, and a salt-wasting tubulopathy. Conventional KCNJ10 knockout mice die within the first two weeks of life due to a severe brain phenotype.

Here, we aimed at investigating the salt-wasting phenotype of KCNJ10 knockout mice in more detail. To induce a kidney-specific KCNJ10 knockout in adult mice, the doxycycline-inducible kidney-specific Cre mouse line (Pax8 rtTA TetOCre) was crossed with a KCNJ10-floxed mouse line. After administration of doxycycline (with the drinking water), the KCNJ10 gene was deleted by Cre-dependent recombination at the KCNJ10-flanking loxP sites.

The success of the deletion was assessed using realtime PCR. Doxycycline treated animals showed up to 90% reduction of renal KCNJ10 expression. The most obvious symptom after induction of the knockout was severe polyuria. The ability to produce concentrated urine upon water restriction was also strongly impaired suggesting that the medullary osmotic gradient was disturbed. Plasma concentrations of sodium, potassium, and chloride were still normal but the plasma pH was alkalotic. Electrolyte analysis of the urine disclosed a renal loss of magnesium and ammonium.

In conclusion, acute induction of the kidney-specific KCNJ10 knockout resulted in severe polyuria and metabolic alkalosis. Similar to human patients, knockout mice showed urinary magnesium wasting. Further studies on these mice are needed to investigate the molecular mechanisms causing electrolyte disturbances and polyuria in more detail.