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

Metabolic Processes Involved in 'Net' Ammonia Generation

The kidney is a net producer of ammonia, and this results from metabolism of amino acids, predominantly glutamine, that results in equimolar NH4 + and HCO3 generation. There also is a complementary mechanism through which kidneys 'recycle' NH4 + and 'regenerate' glutamine. The process involves the enzyme, glutamine synthetase, which catalyzes the reaction as follows: NH4 + + glutamate + ATP -> glutamine + H+ + ADP + Pi. Several previous studies have shown that glutamine synthetase expression is negatively correlated with ammonia excretion, that is, conditions that increase ammonia excretion decrease glutamine synthetase expression, and vice versa. [15,20–24]

A recent study substantially advances our understanding of glutamine synthetase's role in renal ammonia excretion. As previous studies have shown that glutamine synthetase is expressed in cells involved in ammonia production, that is, proximal tubule cells, and cells involved in transepithelial ammonia transport, that is, distal convoluted tubule and intercalated cells, and that glutamine synthetase expression can be differentially regulated in these different cell populations,[20] the authors of this recent study used cell-specific glutamine synthetase deletion to determine the specific role of proximal tubule glutamine synthetase in renal ammonia metabolism. Proximal tubule-specific deletion increased basal ammonia excretion (Fig. 3), consistent with decreased ammonia recycling leading to increased net ammonia generation and excretion.[25] There also was an impaired ability to respond to an acid load,[25] indicating that the ability to alter glutamine synthetase-mediated ammonia recycling is critical to increasing net ammoniagenesis. The findings demonstrate the presence of a 'yin-yang' mechanism regulating 'net' ammoniagenesis, one involving ammonia generation and another involving ammonia recycling. The two mechanisms likely act in concert in order to optimize renal ammonia generation.

Figure 3.

Effect of proximal tubule-specific glutamine synthetase deletion on urinary ammonia excretion. (Left panel) Proximal tubule-specific glutamine synthetase deletion increased basal urinary ammonia excretion significantly. (Right panel) Increased ammonia excretion occurred despite no change in urinary pH. Reproduced with permission [25]. NS, not significant.