Effect of NBCe1 deletion on renal citrate and 2-oxoglutarate handling.
The bicarbonate transporter, NBCe1 (SLC4A4), is necessary for at least two components of the proximal tubule contribution to acid-base homeostasis, filtered bicarbonate reabsorption, and ammonia metabolism. This study's purpose was to determine NBCe1's role in a third component of acid-base homeostasis, organic anion metabolism, by studying mice with NBCe1 deletion. Because NBCe1 deletion causes metabolic acidosis, we also examined acid-loaded wild-type adult mice to determine if the effects of NBCe1 deletion were specific to NBCe1 deletion or were a non-specific effect of the associated metabolic acidosis. Both NBCe1 KO and acid-loading decreased citrate excretion, but in contrast to metabolic acidosis alone, NBCe1 KO decreased expression of the apical citrate transporter, NaDC-1. Thus, NBCe1 expression is necessary for normal NaDC-1 expression, and NBCe1 deletion induces a novel citrate reabsorptive pathway. Second, NBCe1 KO increased 2-oxoglutarate excretion. This could not be attributed to the metabolic acidosis as experimental acidosis decreased excretion. Increased 2-oxoglutarate excretion could not be explained by changes in plasma 2-oxoglutarate levels, the glutaminase I or the glutaminase II generation pathways, 2-oxoglutarate metabolism, its putative apical 2-oxoglutarate transporter, OAT10, or its basolateral transporter, NaDC-3.


CONCLUSIONS
(1) NBCe1 is necessary for normal proximal tubule NaDC-1 expression; (2) NBCe1 deletion results in stimulation of a novel citrate reabsorptive pathway; and (3) NBCe1 is necessary for normal 2-oxoglutarate metabolism through mechanisms independent of expression of known transport and metabolic pathways.
Division of Nephrology, Hypertension and Renal Transplantation, University of Florida College of Medicine, Gainesville, Florida.
Gunars
G
Osis
Division of Nephrology, Hypertension and Renal Transplantation, University of Florida College of Medicine, Gainesville, Florida.
Mary E
ME
Handlogten
Division of Nephrology, Hypertension and Renal Transplantation, University of Florida College of Medicine, Gainesville, Florida.
Hyun-Wook
HW
Lee
Renal Division, Tulane University College of Medicine, New Orleans, Louisiana.
Kathleen S
KS
Hering-Smith
Renal Division, Tulane University College of Medicine, New Orleans, Louisiana.
Weitao
W
Huang
Department of Physiology & Biomedical Engineering and Nephrology & Hypertension, Mayo Clinic College Of Medicine, Rochester, Minnesota.
Michael F
MF
Romero
Division of Nephrology, Hypertension and Renal Transplantation, University of Florida College of Medicine, Gainesville, Florida.
Jill W
JW
Verlander
Division of Nephrology, Hypertension and Renal Transplantation, University of Florida College of Medicine, Gainesville, Florida Nephrology and Hypertension Section, North Florida/South Georgia Veterans Health System, Gainesville, Florida david.weiner@medicine.ufl.edu.
I David
ID
Weiner
D000138:Acidosis / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019343:Citric Acid / Q000378:metabolism*; D015151:Immunoblotting; D007150:Immunohistochemistry; D007656:Ketoglutaric Acids / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D027982:Sodium-Bicarbonate Symporters / Q000235:genetics / Q000378:metabolism*
D007656:Ketoglutaric Acids; C498899:Slc4a4 protein, mouse; D027982:Sodium-Bicarbonate Symporters; D019343:Citric Acid
2‐oxoglutarate; NBCe1; NaDC‐1; acidosis; citrate; proximal tubule