Effects of proximal tubule NBCe1-A deletion on collecting duct intercalated cell responses to hypokalemia.

Hypokalemia activates intercalated cell acid secretion, but because hypokalemia is typically associated with metabolic alkalosis, this activation cannot be ascribed to extracellular pH. Metabolic acidosis induces responses similar to those of hypokalemia, and its effects are blocked by deletion of the proximal tubule Na+-bicarbonate cotransporter, electrogenic, isoform 1, variant A (NBCe1-A). This response likely involves ammonia: metabolic acidosis stimulates ammoniagenesis through an NBCe1-A-dependent mechanism, and ammonia stimulates collecting duct acid secretion. Since hypokalemia also stimulates ammoniagenesis through an NBCe1-A-dependent mechanism, we postulated that a similar proximal tubule NBCe1-A-dependent mechanism underlies hypokalemia's effect on collecting duct intercalated cells. To test this, we induced hypokalemia by providing a nominally K+-free diet for 4 days to wild-type (WT) and NBCe1-A deletion (KO) mice. Hypokalemia increased % of cortical collecting duct (CCD) type A intercalated cells (A-cells), decreased % of CCD type B intercalated cells (B-cells), increased cortical anion exchanger 1 (AE1) expression, increased % of A-cells in the inner stripe of the outer medullary collecting duct (OMCDis), increased OMCDis A-cell height, increased apical polarization of OMCDis A-cell H+-ATPase, and increased OMCDis AE1 expression. NBCe1-A deletion inhibited each of these responses. Hypokalemia reduced B-cell pendrin abundance; this was NBCe1-A-independent, whereas the reduction to metabolic acidosis was NBCe1-A-dependent in a previous study. We conclude that the proximal tubule, through an NBCe1-A-dependent mechanism likely involving ammonia, regulates the A-cell acid-secretory response to hypokalemia. Because a similar paradigm is present in the response to metabolic acidosis, this may represent a generalized pathway regulating collecting duct acid secretion.NEW & NOTEWORTHY The collecting duct response to hypokalemia is not innate to the collecting duct, which is paradoxical from an acid-base perspective, and instead requires proximal tubule-dependent NBCe1-A-dependent signaling to occur.