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

Liping Liu, Miriam Zacchia, Xuefei Tian, Laxiang Wan, Aiji Sakamoto, Masashi Yanagisawa, Robert J. Alpern, Patricia A. Preisig

Research output: Contribution to journalArticlepeer-review

22 Scopus citations


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 (ETB) receptor antagonist, BQ788. Acid feeding had no effect on brush border membrane NaDC-1 activity in mice in which ETB receptor expression was knocked out, whereas a stimulatory effect was found in wild-type mice. Using ET A/ETB chimeric and ETB C-terminal tail truncated constructs, ET-1 stimulation of NaDC-1 required a receptor C-terminal tail from either ET A or ETB. The ET-1 effect was greatest when either the ETB transmembrane domain and C-terminal tail were present or the ETB C-terminal tail was linked to the ET A transmembrane domain. This effect was smaller when the ETB 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 ETB 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.

Original languageEnglish (US)
Pages (from-to)895-904
Number of pages10
JournalKidney international
Issue number9
StatePublished - Nov 2010


  • cell and transport physiology
  • cell signaling
  • chronic metabolic acidosis
  • citraturia
  • renal proximal tubule cell

ASJC Scopus subject areas

  • Nephrology


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