Acid regulation of NaDC-1 requires a functional endothelin B receptor.
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.
Liu
Liping
L
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 06520-8029, USA.
Zacchia
Miriam
M
Tian
Xuefei
X
Wan
Laxiang
L
Sakamoto
Aiji
A
Yanagisawa
Masashi
M
Alpern
Robert J
RJ
Preisig
Patricia A
PA
D000138:Acidosis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D029382:Dicarboxylic Acid Transporters / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008871:Microvilli / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D009893:Opossums; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D027981:Symporters / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
D029382:Dicarboxylic Acid Transporters; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D009842:Oligopeptides; D029363:Organic Anion Transporters, Sodium-Dependent; D010880:Piperidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D011993:Recombinant Fusion Proteins; C490479:Slc13a2 protein, mouse; D027981:Symporters; C086539:BQ 788