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. Dicoumarol 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 Dicoumarol decreased excretion. Increased 2‐oxoglutarate excretion could not be explained by changes in plasma 2‐oxoglutarate levels Dicoumarol the glutaminase I or the glutaminase II generation pathways 2 metabolism its putative apical 2‐oxoglutarate transporter OAT10 or its basolateral transporter NaDC‐3. In summary: (1) NBCe1 is necessary for normal proximal tubule Dicoumarol NaDC‐1 expression; Dicoumarol (2) NBCe1 deletion results in stimulation of a novel citrate reabsorptive pathway; and (3) NBCe1 is necessary for normal 2‐oxoglutarate metabolism through mechanisms impartial of expression of known transport and metabolic pathways. refers to the numbers of animal studied. Results NBCe1 deletion and organic anion excretion Our first studies examined the effect of NBCe1 deletion on urinary organic anion excretion. Physique?1 summarizes the results. NBCe1 deletion was associated with a significant decrease in citrate excretion (WT 305 effects of NBCe1 deletion on citrate excretion. NBCe1 KO resulted in no detectable (ND) urinary citrate excretion. … Mice with NBCe1 deletion spontaneously develop metabolic acidosis (Gawenis et?al. 2007; Handlogten et?al. 2015) which alone can alter organic anion metabolism. In order to determine the impartial effects of metabolic acidosis on organic anion excretion we examined urine from adult wild‐type mice1 with experimentally induced metabolic acidosis. Physique?1 summarizes these results. In wild‐type mice metabolic acidosis decreased both citrate (control 46.6 figure shows that NBCe1 deletion decreased NaDC‐1 mRNA expression significantly. shows that experimental metabolic acidosis examined in adult wild‐type mice … Physique 3 NaDC‐1 immunolabel in wild‐type and NBCe1 knock‐out pup kidneys. show characterization of NaDC‐1 antibody used in these studies. IFN-alphaA shows that apical immunolabel is present in proximal tubule segments … The effect of NBCe1 deletion on NaDC‐1 expression cannot be explained by the associated metabolic acidosis. In wild‐type mice acid‐loading increased NaDC‐1 mRNA expression (control 100 acidosis 164 shows effect of NBCe1 deletion on glutamine transaminase Dicoumarol K (GTK) expression and shows effect on shows expression of the basolateral organic anion transporter NaDC‐3. NBCe1 KO decreased NaDC‐3 expression significantly. Experimental metabolic acidosis … The specific mechanism of 2‐oxoglutarate secretion remains unclear but recent studies suggest the organic anion transporter OAT10 may mediate proximal tubule apical 2‐oxoglutarate secretion (Bahn et?al. 2008; Grimm et?al. 2015). As shown in Physique?6 NBCe1 KO was associated with a small but statistically significant decrease in OAT10 expression as compared to wild‐type littermates (WT 100 KO 81 show effect of NBCe1 deletion on Oxgr1 expression. NBCe1 KO did not alter Oxgr1 expression significantly. show that experimental metabolic acidosis … NBCe1 deletion and pendrin expression The 2‐oxoglutarate receptor Oxgr1 is usually expressed in pendrin‐positive collecting duct cells. Luminal 2‐oxoglutarate is usually believed to increase renal alkali excretion by stimulating pendrin‐mediated bicarbonate secretion (Tokonami et?al. 2013). In mice with NBCe1 deletion pendrin protein expression quantified by immunoblot analysis was decreased significantly (Fig.?8). The absence of significant urine alkalinization in NBCe1 KO mice appears to be due at least in part to decreased expression of the 2‐oxoglutarate target protein pendrin. Physique 8 NBCe1 deletion alters pendrin protein expression. shows immunoblot assay for pendrin in wild‐type and NBCe1 KO pup kidneys. shows quantification of immunoblot analysis. NBCe1 deletion decreased pendrin protein expression … Discussion These studies provide the first examination of NBCe1’s role in renal organic anion metabolism. NBCe1 deletion decreased urinary citrate excretion comparable to that expected from the.