Plasma Potassium Determines NCC Abundance in Adult Kidney-Specific γENaC Knockout

Abstract

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 <i>α</i>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 <i>α</i>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 <i>γ</i>ENaC subunit in the PHA-I phenotype. Nephron-specific <i>γ</i>ENaC knockout mice also presented with salt-wasting syndrome and severe hyperkalemia. Unlike mice lacking <i>α</i>ENaC or <i>β</i>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 <i>γ</i>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 <i>β</i>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 <i>γ</i>ENaC-deficient mice.