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. In summary: (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.