Mutations of the inwardly rectifying K⁺ channel subunit Kir4.1 (KCNJ10) are causative for an autosomal recessive disease, which is characterized by epilepsy, ataxia, sensorineural deafness, and a salt-wasting renal tubulopathy (EAST or SeSAME syndrome). The Kir4.1 subunit is believed to form heteromeric K⁺ channels with Kir5.1 in the kidney. The aim of this study was to investigate the physiological and pathophysiological relevance of the Kir5.1 subunit and the Kir4.1/Kir5.1 heteromeric channel for kidney function.

To study the role of the Kir5.1 subunit conventional Kir5.1 knockout (Kir5.1^-/-) SV129 mice were used. Under normal diet Kir5.1^-/- mice developed normal and did not exhibit growth retardation or apparent morphological abnormalities. Immunofluorescence stains and real-time PCR experiments showed that Kir5.1 is mainly expressed in the kidney, stomach, thyroid and brain of Kir5.1^+/+ mice. The localization of Kir5.1 in renal tubules is restricted to the basolateral membrane of the distal convoluted tubule, the connecting tubule and the cortical collecting duct. Previous studies showed that Kir5.1^-/-C57BL/6Jmice exhibit hypercalciuria, hypermagnesiuria and a high renal loss of K⁺ but normal Na⁺ excretion (Paulais M, et al. PNAS 2011). Our experiments with adult Kir5.1^-/-SV129mice confirmed these data. In contrast, infantile Kir5.1^-/-SV129mice showed a strongly diminished renal K⁺ excretion and a high loss of Na⁺ via the urine.

These data indicate that Kir5.1 regulates renal electrolyte transport in the distal nephron in a complex and age-dependent way. The underlying mechanisms await further investigation.