Beschreibung: The gene SLC4A5 encodes the Na + -HCO 3 – cotransporter electrogenic 2, which is located in the distal nephron. Genetically deleting Na + -HCO 3 – cotransporter electrogenic 2 (knockout) causes Na + -retention and hypertension, a phenotype that is diminished with alkali loading. We performed experiments with acid-loaded mice and determined whether overactive epithelial Na + channels (ENaC) or the Na + -Cl – cotransporter causes the Na + retention and hypertension in knockout. In untreated mice, the mean arterial pressure was higher in knockout, compared with wild-type (WT); however, treatment with amiloride, a blocker of ENaC, abolished this difference. In contrast, hydrochlorothiazide, an inhibitor of Na + -Cl – cotransporter, decreased mean arterial pressure in WT, but not knockout. Western blots showed that quantity of plasmalemmal full-length ENaC-α was significantly higher in knockout than in WT. Amiloride treatment caused a 2-fold greater increase in Na + excretion in knockout, compared with WT. In knockout, but not WT, amiloride treatment decreased plasma [Na + ] and urinary K + excretion, but increased hematocrit and plasma [K + ] significantly. Micropuncture with microelectrodes showed that the [K + ] was significantly higher and the transepithelial potential (V te ) was significantly lower in the late distal tubule of the knockout compared with WT. The reduced V te in knockout was amiloride sensitive and therefore revealed an upregulation of electrogenic ENaC-mediated Na + reabsorption in this segment. These results show that, in the absence of Na + -HCO 3 – cotransporter electrogenic 2 in the late distal tubule, acid-loaded mice exhibit disinhibition of ENaC-mediated Na + reabsorption, which results in Na + retention, K + wasting, and hypertension.