Increased epithelial sodium channel activity contributes to hypertension caused by Na⁺-HCO₃^- cotransporter electrogenic 2 deficiency

The gene SLC4A5 encodes the Na⁺-HCO₃^- cotransporter electrogenic 2, which is located in the distal nephron. Genetically deleting Na⁺-HCO₃^- 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⁺-HCO₃^- 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.