Plasma Potassium Determines NCC Abundance in Adult Kidney-Specific ENaC Knockout.

The amiloride-sensitive epithelial sodium channel (ENaC) and the thiazide-sensitive sodium chloride cotransporter (NCC) are key regulators of sodium and potassium and colocalize in the late distal convoluted tubule of the kidney. Loss of the ENaC subunit leads to a perinatal lethal phenotype characterized by sodium loss and hyperkalemia resembling the human syndrome pseudohypoaldosteronism type 1 (PHA-I). In adulthood, inducible nephron-specific deletion of ENaC in mice mimics the lethal phenotype observed in neonates, and as in humans, this phenotype is prevented by a high sodium (HNa)/low potassium (LK) rescue diet. Rescue reflects activation of NCC, which is suppressed at baseline by elevated plasma potassium concentration. In this study, we investigated the role of the ENaC subunit in the PHA-I phenotype. Nephron-specific ENaC knockout mice also presented with salt-wasting syndrome and severe hyperkalemia. Unlike mice lacking ENaC or ΕΝaC, an HNa/LK diet did not normalize plasma potassium (K) concentration or increase NCC activation. However, when K was eliminated from the diet at the time that ENaC was deleted, plasma K concentration and NCC activity remained normal, and progressive weight loss was prevented. Loss of the late distal convoluted tubule, as well as overall reduced ENaC subunit expression, may be responsible for the more severe hyperkalemia. We conclude that plasma K concentration becomes the determining and limiting factor in regulating NCC activity, regardless of Na balance in ENaC-deficient mice.