Recent Advances in Understanding Renal Ammonia Metabolism and Transport

I. David Weiner; Jill W. Verlander


Curr Opin Nephrol Hypertens. 2016;25(5):436-443. 

In This Article

Regulation of Ammonia Generation

The recent finding that expression of the proximal tubule basolateral bicarbonate transporter, NBCe1, is necessary for normal renal ammonia metabolism is an important advance in understanding the mechanisms regulating ammonia generation. Proximal tubule NBCe1 mediates coupled cotransport of Na+ with three HCO3 equivalents, and is the primary mechanism of proximal tubule basolateral bicarbonate exit, and genetic abnormalities in it are the major genetic cause of proximal RTA.[26] NBCe1 deletion causes metabolic acidosis,[27,28] which should increase ammonia excretion, yet recent studies show that NBCe1 deletion decreased ammonia excretion (Fig. 4).[28] This occurred despite intact urine acidification and intact expression of the collecting duct ammonia transport proteins, Rhbg and Rhcg.[28] Decreased ammonia excretion appeared to result from abnormal expression of multiple enzymes involved in ammonia metabolism. There was decreased expression of the major proximal tubule enzymes involved in ammonia generation, PDG, glutamate dehydrogenase and PEPCK, and increased expression of the ammonia recycling protein, glutamine synthetase,[28,29] responses, opposite that expected from metabolic acidosis. Thus, NBCe1 expression is necessary for normal proximal tubule ammonia metabolism.

Figure 4.

Effect of NBCe1 deletion on urinary ammonia and pH. (Top) Effects on urine ammonia. Despite the metabolic acidosis associated with NBCe1 gene deletion, ammonia excretion decreased with heterozygous gene deletion and was suppressed significantly further with homozygous deletion. (Bottom) Effects on urine pH. Urine pH was significantly more acidic (lower) in mice with heterozygous NBCe1 deletion than in wild-type mice and was decreased significantly further by homozygous NBCe1 deletion. Reproduced with permission [28]. Het, heterozygous gene deletion; KO, homozygous NBCe1 deletion (knock-out); Wt, wild-type.

In addition to being necessary for normal ammonia metabolism, NBCe1 may also be important for organic anion transport. NBCe1 deletion caused abnormal regulation of expression of the primary proximal tubule citrate transporter, NaDC1 (Fig. 5).[29] This did not alter net citrate excretion, possibly because of increased activity of a previously described acid-stimulated, calcium-sensitive citrate transport activity.[30] Excretion of another important organic anion, 2-oxoglutarate (also known as α-ketoglutarate), was also altered by NBCe1 deletion. Specifically, NBCe1 deletion dramatically increased 2-oxoglutarate excretion.[29] The change in 2-oxoglutarate excretion could not be ascribed to the accompanying metabolic acidosis, as experimental metabolic acidosis in wild-type mice actually decreased 2-oxoglutarate excretion,[29] as previously described by others.[31,32] Thus, NBCe1 is necessary for normal proximal tubule bicarbonate reabsorption, and also for two other major roles of the proximal tubule in acid–base homeostasis, namely ammonia generation and organic anion transport/metabolism.

Figure 5.

Effect of NBCe1 deletion on NaDC1 expression. NaDC1 is an apical Na+-coupled dicarboxylate (including citrate) transporter present in the proximal tubule that is thought to be the primary mechanism regulating urinary citrate excretion. NBCe1 deletion decreased NaDC1 mRNA (left panels) and immunolabel expression (right panels). The effect was unrelated to the associated metabolic acidosis, as experimental metabolic acidosis in the absence of NBCe1 gene deletion increased NaDC1 mRNA and immunolabel expression. Reproduced with permission [29]. KO, homozygous NBCe1 deletion (knock-out); Wt, wild-type.