Severe hyperkalemia is rescued by low-potassium diet in renal βENaC-deficient mice

In adulthood, an induced nephron-specific deficiency of αENaC (Scnn1a) resulted in pseudohypoaldosteronism type 1 (PHA-1) with sodium loss, hyperkalemia, and metabolic acidosis that is rescued through high-sodium/low-potassium (HNa⁺/LK⁺) diet. In the present study, we addressed whether renal βENaC expression is required for sodium and potassium balance or can be compensated by remaining (α and γ) ENaC subunits using adult nephron-specific knockout (Scnn1b^Pax8/LC1) mice. Upon induction, these mice present a severe PHA-1 phenotype with weight loss, hyperkalemia, and dehydration, but unlike the Scnn1a^Pax8/LC1 mice without persistent salt wasting. This is followed by a marked downregulation of STE20/SPS1-related proline-alanine-rich protein kinase (SPAK) and Na⁺/Cl^- co-transporter (NCC) protein expression and activity. Most of the experimental Scnn1b^Pax8/LC1 mice survived with a HNa⁺/LK⁺ diet that partly normalized NCC phosphorylation, but not total NCC expression. Since salt loss was minor, we applied a standard-sodium/LK⁺ diet that efficiently rescued these mice resulting in normokalemia and normalization of NCC phosphorylation, but not total NCC expression. A further switch to LNa⁺/standard-K⁺ diet induced again a severe PHA-1-like phenotype, but with only transient salt wasting indicating that low-K⁺ intake is critical to decrease hyperkalemia in a NCC-dependent manner. In conclusion, while the βENaC subunit plays only a minor role in sodium balance, severe hyperkalemia results in downregulation of NCC expression and activity. Our data demonstrate the importance to primarily correct the hyperkalemia with a low-potassium diet that normalizes NCC activity.

Epithelial sodium channel; Hyperkalemia; Pseudohypoaldosteronism type 1; STE20/SPS1-related proline-alanine-rich protein kinase; Thiazide-sensitive Na+/Cl− co-transporter.