Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCB141

Poster Communications

The role of the inwardly rectifying potassium channel Kir5.1 in the distal convoluted tubule

C. Quintanova2,1, A. Forst2, R. Warth2

1. Institut of Physiology, Christian-Albrechts-Universität zu Kiel, Kiel, Germany. 2. University of Regensburg, Regensburg, Germany.


The kidneys are essential for regulating the volume and electrolyte homeostasis. Potassium (K+) is the most abundant cation in intracellular fluid and plays an important role in maintaining membrane potential across the membrane. In the basolateral membrane of the distal convoluted tubule (DCT) KCNJ10 (Kir4.1) - a member of the inwardly rectifying K+ channel (Kir) family. Kir4.1 is able to form homotetramers or heterotetramers with its close homologous KCNJ16 (Kir5.1). The relevance of Kir4.1 in the DCT was highlighted by the loss-of-function mutations in KCNJ10 which result in the EAST/SeSAME-syndrome (acronym for epilepsy, ataxia, sensorineural deafness, and salt-wasting tubulopathy), a complex disease with renal salt wasting, hypokalemic metabolic alkalosis, hypomagnesemia and hypocalciuria. However, the role of Kir5.1 is relatively unknown and the Kir5.1-/- (C57BL/6J) mice exhibit a renal phenotype that is the opposite to the one of KCNJ10 except for the hypokalemia.(1) It has been suggested that Kir5.1 in combination with Kir4.1 might act as basolateral K+-sensors in the DCT modifying K+ secretion in the late distal nephron by indirectly regulating of the activity of the apical sodium-chloride (Na+/Cl-) symporter NCC.(2) Here, we reinvestigated the expression and distribution of KCNJ16 in the kidney by analyzing manually sorted tubular segments using quantitative real time PCR. Expression of KCNJ16 was highest in proximal tubules and DCT. This data was confirmed by KCNJ16-promotor-driven X-gal staining in Kir5.1-/- mouse kidneys. To test whether Kir5.1 might indeed be a K+ sensor in the DCT as hypothesized by Terker et al. (2), we isolated murine DCTs and exposed them to changes in basolateral and apical K+. Fura-2 mediated Ca2+-measurements revealed that only basolateral, but not apical, application of low K+ solution translated into increased intracellular Ca2+ levels. However, deletion of Kir5.1 did not alter the Ca2+ signals suggesting that Kir5.1 channels are not essential for this component of the K+ sensing mechanism. To further study the effect of KCNJ16 deletion in mice, we analyzed renal electrolyte handling in those mice. Under control diet, Kir5.1-/- mice revealed hypokalemia and hypermagnesuria and when challenged with a high Na+ diet they revealed a massive increased excretion of electrolytes which suggests an impaired adaptation capacity of electrolyte balance. Our analysis of the Kir5.1-/- mice indicates a crucial role for Kir5.1 in renal electrolyte balance although Kir5.1 seems nonessential for K+ sensing in the DCT.

Where applicable, experiments conform with Society ethical requirements