NBCe1 expression is required for normal renal ammonia metabolism

Am J Physiol Renal Physiol. 2015 Oct 1;309(7):F658-66. doi: 10.1152/ajprenal.00219.2015. Epub 2015 Jul 29.


The mechanisms regulating proximal tubule ammonia metabolism are incompletely understood. The present study addressed the role of the proximal tubule basolateral electrogenic Na(+)-coupled bicarbonate cotransporter (NBCe1; Slc4a4) in renal ammonia metabolism. We used mice with heterozygous and homozygous NBCe1 gene deletion and compared these mice with their wild-type littermates. Because homozygous NBCe1 gene deletion causes 100% mortality before day 25, we studied mice at day 8 (±1 day). Both heterozygous and homozygous gene deletion caused a gene dose-related decrease in serum bicarbonate. The ability to lower urinary pH was intact, and even accentuated, with NBCe1 deletion. However, in contrast to the well-known effect of metabolic acidosis to increase urinary ammonia excretion, NBCe1 deletion caused a gene dose-related decrease in ammonia excretion. There was no identifiable change in proximal tubule structure by light microscopy. Examination of proteins involved in renal ammonia metabolism showed decreased expression of phosphate-dependent glutaminase and phosphoenolpyruvate carboxykinase, key enzymes in proximal tubule ammonia generation, and increased expression of glutamine synthetase, which recycles intrarenal ammonia and regenerates glutamine. Expression of key proteins involved in ammonia transport outside of the proximal tubule (rhesus B glycoprotein and rhesus C glycoprotein) was not significantly changed by NBCe1 deletion. We conclude from these findings that NBCe1 expression is necessary for normal proximal tubule ammonia metabolism.

Keywords: acid-base; ammonia; electrogenic sodium-coupled bicarbonate cotransporter 1; proximal tubule.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Ammonia / metabolism*
  • Animals
  • Bicarbonates / blood
  • Blotting, Western
  • Gene Deletion
  • Immunohistochemistry
  • Kidney / metabolism*
  • Kidney Tubules, Collecting / metabolism
  • Kidney Tubules, Proximal / metabolism
  • Mice
  • Mice, Knockout
  • Potassium / blood
  • Sodium / blood
  • Sodium-Bicarbonate Symporters / biosynthesis
  • Sodium-Bicarbonate Symporters / genetics
  • Sodium-Bicarbonate Symporters / metabolism*
  • Sodium-Hydrogen Exchanger 3
  • Sodium-Hydrogen Exchangers / biosynthesis
  • Sodium-Hydrogen Exchangers / genetics


  • Bicarbonates
  • Slc4a4 protein, mouse
  • Sodium-Bicarbonate Symporters
  • Sodium-Hydrogen Exchanger 3
  • Sodium-Hydrogen Exchangers
  • Ammonia
  • Sodium
  • Potassium