Defective bicarbonate reabsorption in Kir4.2 potassium channel deficient mice impairs acid-base balance and ammonia excretion

ABSTRACT The kidneys excrete the daily acid load mainly by generating and excreting ammonia but the underlying molecular mechanisms are not fully understood. Here we evaluated the role of the inwardly rectifying potassium channelsubunit Kir4.2 ( Kcnj15gene product) in this process. In mice, Kir4.2 was present exclusively at the basolateral membrane of proximaltubular cells and disruption of Kcnj15caused a hyperchloremic metabolic acidosisassociated with a reduced threshold for bicarbonate in the absence of a generalized proximal tubuledysfunction. Urinary ammonium excretion rates in Kcnj15- deleted mice were inappropriate to acidosisunder basal and acid-loading conditions, and not related to a failure to acidify urine or a reduced expression of ammonia transportersin the collecting duct. In contrast, the expression of key proteins involved in ammonia metabolism and secretion by proximalcells, namely the glutamine transporter SNAT3, the phosphate-dependent glutaminaseand phosphoenolpyruvate carboxykinaseenzymes, and the sodium-proton exchanger NHE-3 was inappropriate in Kcnj15-deleted mice. Additionally, Kcnj15deletion depolarized the proximalcell membrane by decreasing the barium-sensitive component of the potassium conductance and caused an intracellular alkalinization. Thus, the Kir4.2 potassium channelsubunit is a newly recognized regulator of proximalammonia metabolism. The kidney consequences of its loss of function in mice support the proposal for KCNJ15as a molecular basis for human isolated proximal renal tubular acidosis.