Proximal Tubule Regulates the Collecting Duct Response to Hypokalemia

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Background: Hypokalemia induces phenotypic and remodeling responses in the collecting duct that increase net acid excretion. We showed recently that the proximal tubule, through an NBCe1-A-dependent signaling pathway likely involving ammonia, regulates the collecting duct response to metabolic acidosis. Because hypokalemia stimulates proximal tubule NBCe1-A-dependent ammoniagenesis, we postulated that a similar mechanism would control the collecting duct response to hypokalemia. Methods: Male and female NBCe1-A knock-out (KO) and wild-type (WT) mice were studied either on a K-control diet or a nominally K-free diet (KFD). Immunoblot analysis, immunohistochemistry, and cell counting evaluated phenotypic and remodeling responses. Results: KO mice tolerated only four days of KFD before developing life-threatening hypokalemia. After four days, KFD increased the number of Type A intercalated cells (A-cell) in the inner stripe of the outer medullary collecting duct (OMCDis) and decreased the number of Type B intercalated cells (B-Cell) in the cortical collecting duct (CCD), and KO significantly blocked these remodeling responses. KFD increased the number of A-cells in the CCD, and KO did not alter this response. Immunoblot analysis showed KFD decreased cortical pendrin expression, and KO did not alter this response. In the inner stripe of the outer medulla (ISOM), KFD did not significantly alter either AE1 or Rh B Glycoprotein (Rhbg) expression, and NBCe1-A deletion did not alter the response to KFD. ANOVA analysis showed no significant effect of sex on these immunoblot responses. Conclusions: We conclude: (1) the CCD B-Cell and OMCDis A-cell remodeling responses to hypokalemia are present at four days and involves a proximal tubule NBCe1-A-dependent response likely involving ammonia; (2) the ISOM collecting duct phenotypic response to hypokalemia that involves AE1 and Rhbg requires more than four days to develop; and, (3) the CCD pendrin response to hypokalemia occurs more rapidly than ISOM responses, and is independent of proximal tubule NBCe1-A expression. Funding: NIDDK Support

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