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

Dietary Protein and Ammonia Metabolism

Decreased dietary protein intake has multiple benefits for patients with CKD. In addition, protein intake is a major determinant of endogenous acid production, and thus it is necessary that urinary ammonia excretion change in parallel with protein intake. A recent study[15] has addressed the effect of dietary protein on ammonia metabolism in detail. Dietary protein restriction decreased urinary ammonia excretion by approximately 85% within 2 days. Expression of phosphate-dependent glutaminase (PDG) and phosphoenolpyruvate carboxykinase (PEPCK), key proteins involved in ammonia generation, decreased, whereas expression of the ammonia recycling protein, glutamine synthetase, increased.[15] Importantly, none of the individual changes could account quantitatively for the degree of decreased ammonia excretion; it was the coordinated effect that appeared to be necessary. Also, decreased glutamine synthetase expression could have an important role in nitrogen conservation in response to dietary protein restriction. Thus, dietary protein restriction induces coordinated expression consistent with decreasing urinary ammonia excretion.

Another, slightly older, study examined the converse condition, the response to high dietary protein intake, and showed that it was the metabolism to generate fixed acids, not the nitrogen content, that was responsible for the increased ammonia excretion. Second, it demonstrated increased expression of two key proteins involved in ammonia generation, glutamine transporter, SN1, and PDG.[16] Rhcg mRNA expression increased, and Rhcg gene deletion showed that Rhcg expression was necessary for the initial increase in ammonia excretion.[16] Rhcg's role in the response to high protein diet contrasted with a lack of necessity for Rhcg in the response to dietary protein restriction.[15]

The two studies, when taken together, indicate that changes in dietary protein induce coordinated changes in many aspects of renal ammonia metabolism. Whether the minor differences in the responses involved in adaptation to low versus high protein diet reflect fundamental differences or minor variations associated with slightly different models and mice cannot be differentiated at this time.

An unexpected finding in the studies of dietary protein restriction is related to the ammonia transporter family member, Rhbg. Dietary protein restriction, even though it decreased ammonia excretion, increased Rhbg expression in intercalated cells in the inner stripe of the outer medullary collecting duct.[15] In general, Rhbg expression parallels changes in ammonia excretion, and thus the observation of increased Rhbg expression in a state of decreased ammonia excretion was not predicted. Increased Rhbg expression, however, did not appear necessary for the increase in ammonia excretion, as collecting duct-specific Rhbg deletion did not alter the response to dietary protein restriction.[15] This observation suggests that Rhbg has an yet unidentified biological role in addition to its contribution to transepithelial ammonia transport.