Acid regulation of NaDC-1 requires a functional endothelin B receptor

Kidney Int. 2010 Nov;78(9):895-904. doi: 10.1038/ki.2010.264. Epub 2010 Aug 11.


Metabolically generated acid is the major physiological stimulus for increasing proximal tubule citrate reabsorption, which leads to a decrease in citrate excretion. The activity of the Na-citrate cotransporter, NaDC-1, is increased in vivo by acid ingestion and in vitro by an acidic pH medium. In opossum kidney cells the acid stimulatory effect and the ability of endothelin-1 (ET-1) to stimulate NaDC-1 activity are both blocked by the endothelin B (ET(B)) receptor antagonist, BQ788. Acid feeding had no effect on brush border membrane NaDC-1 activity in mice in which ET(B) receptor expression was knocked out, whereas a stimulatory effect was found in wild-type mice. Using ET(A)/ET(B) chimeric and ET(B) C-terminal tail truncated constructs, ET-1 stimulation of NaDC-1 required a receptor C-terminal tail from either ET(A) or ET(B). The ET-1 effect was greatest when either the ET(B) transmembrane domain and C-terminal tail were present or the ET(B) C-terminal tail was linked to the ET(A) transmembrane domain. This effect was smaller when the ET(B) transmembrane domain was linked to the ET(A) C-terminal tail. Thus, the acid-activated pathway mediating stimulation of NaDC-1 activity requires a functional ET(B) receptor in vivo and in vitro, as does acid stimulation of NHE3 activity. Since increased NaDC-1 and NHE3 activities constitute part of the proximal tubule adaptation to an acid load, these studies indicate that there are similarities in the signaling pathway mediating these responses.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acidosis / genetics
  • Acidosis / metabolism*
  • Animals
  • Biological Transport
  • Cell Line
  • Dicarboxylic Acid Transporters / genetics
  • Dicarboxylic Acid Transporters / metabolism
  • Disease Models, Animal
  • Endothelin B Receptor Antagonists
  • Endothelin-1 / metabolism
  • Hydrogen-Ion Concentration
  • Kidney / drug effects
  • Kidney / metabolism*
  • Mice
  • Mice, Knockout
  • Microvilli / metabolism
  • Oligopeptides / pharmacology
  • Opossums
  • Organic Anion Transporters, Sodium-Dependent / genetics
  • Organic Anion Transporters, Sodium-Dependent / metabolism
  • Piperidines / pharmacology
  • Protein Structure, Tertiary
  • Receptor, Endothelin A / metabolism
  • Receptor, Endothelin B / genetics
  • Receptor, Endothelin B / metabolism*
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction
  • Symporters / genetics
  • Symporters / metabolism
  • Time Factors
  • Transfection


  • Dicarboxylic Acid Transporters
  • Endothelin B Receptor Antagonists
  • Endothelin-1
  • Oligopeptides
  • Organic Anion Transporters, Sodium-Dependent
  • Piperidines
  • Receptor, Endothelin A
  • Receptor, Endothelin B
  • Recombinant Fusion Proteins
  • Slc13a2 protein, mouse
  • Symporters
  • BQ 788