title: NBCe1 expression is required for normal renal ammonia metabolism.
abstract: 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.
authors.affiliation: Division of Nephrology, Hypertension and Renal Transplantation, University of Florida College of Medicine, Gainesville, Florida;
authors.forename: Mary E
authors.initials: ME
authors.lastname: Handlogten
authors.affiliation: Division of Nephrology, Hypertension and Renal Transplantation, University of Florida College of Medicine, Gainesville, Florida;
authors.forename: Gunars
authors.initials: G
authors.lastname: Osis
authors.affiliation: Division of Nephrology, Hypertension and Renal Transplantation, University of Florida College of Medicine, Gainesville, Florida;
authors.forename: Hyun-Wook
authors.initials: HW
authors.lastname: Lee
authors.affiliation: Department of Physiology and Biomedical Engineering and Nephrology and Hypertension, Mayo Clinic College Of Medicine, Rochester, Minnesota; and.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Romero
authors.affiliation: Division of Nephrology, Hypertension and Renal Transplantation, University of Florida College of Medicine, Gainesville, Florida;
authors.forename: Jill W
authors.initials: JW
authors.lastname: Verlander
authors.affiliation: Division of Nephrology, Hypertension and Renal Transplantation, University of Florida College of Medicine, Gainesville, Florida; Nephrology and Hypertension Section, Gainesville Veterans Administration Medical Center, Gainesville, Florida David.Weiner@medicine.ufl.edu.
authors.forename: I David
authors.identifier: http://orcid.org/0000-0002-0046-0600
authors.initials: ID
authors.lastname: Weiner
mesh_terms: D000641:Ammonia / Q000378:metabolism*; D000818:Animals; D001639:Bicarbonates / Q000097:blood; D015153:Blotting, Western; D017353:Gene Deletion; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism*; D007685:Kidney Tubules, Collecting / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011188:Potassium / Q000097:blood; D012964:Sodium / Q000097:blood; D027982:Sodium-Bicarbonate Symporters / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000096:biosynthesis / Q000235:genetics
chemical_list: D001639:Bicarbonates; C498899:Slc4a4 protein, mouse; D027982:Sodium-Bicarbonate Symporters; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D000641:Ammonia; D012964:Sodium; D011188:Potassium
keywords: acid-base; ammonia; electrogenic sodium-coupled bicarbonate cotransporter 1; proximal tubule