NBCe1-A is Required for the Renal Ammonia and Potassium Response to Hypokalemia.

Abstract

Hypokalemia increases ammonia excretion and decreases K+ excretion. The current studies examine the role of the proximal tubule protein, NBCe1-A, in these responses. We studied mice with NBCe1-A deletion (KO) and their wild-type (WT) littermates provided either K+-control or K+-free diet. We also used tissue sections to determine the effect of extracellular ammonia on NCC phosphorylation. A K⁺-free diet significantly increased proximal tubule NBCe1-A and ammonia excretion in WT mice, and NBCe1-A deletion blunted the ammonia excretion response. NBCe1-A deletion inhibited the ammoniagenic/ammonia-recycling enzyme response in the cortical proximal tubule (PT), where NBCe1-A is present in WT mice. In the outer medulla, where NBCe1-A is not present, the PT ammonia metabolism response was accentuated by NBCe1-A deletion. KO mice developed more severe hypokalemia and had greater urinary K+ excretion during a K⁺-free diet than did WT mice. This was associated with blunting of the hypokalemia-induced change in NCC phosphorylation. NBCe1-A KO mice have systemic metabolic acidosis, but experimentally induced metabolic acidosis did not alter NCC phosphorylation. Although KO mice have impaired ammonia metabolism, studies in tissue sections show that lack of ammonia does impair NCC phosphorylation. Finally, urinary aldosterone was greater in KO than in WT mice, but neither expression of ENaC α, β and γ subunits nor of H+-K+-ATPase α1 or α2 subunits correlated with changes in urinary K+. We conclude that NBCe1-A is a critical for the effect of diet-induced hypokalemia to increase cortical proximal tubule ammonia generation and for the expected decrease in urinary K+ excretion.