As part of a study on the regulation of renal ammoniagenesis in the mouse kidney, we investigated the effect of chronic
metabolic acidosis on
glutamine synthesis by isolated mouse renal proximal tubules. The results obtained reveal that, in tubules from control mice,
glutamine synthesis occurred at high rates from
glutamate and
proline and, to a lesser extent, from
ornithine,
alanine, and
aspartate. A 48 h,
metabolic acidosis caused a marked inhibition of
glutamine synthesis from near-physiological concentrations of both
alanine and
proline that were avidly metabolized by the tubules;
metabolic acidosis also greatly stimulated
glutamine utilization and metabolism. These effects were accompanied by a large increase (i) in
alanine,
proline, and
glutamine gluconeogenesis and (ii) in
ammonia accumulation from
proline and
glutamine. In the renal cortex of acidotic mice, the activity of
phosphoenolpyruvate carboxykinase increased 4-fold, but that of
glutamate dehydrogenase did not change; in contrast with what is known in the rat renal cortex,
metabolic acidosis markedly diminished the
glutamine synthetase activity and
protein level, but not the
glutamine synthetase mRNA level in the mouse renal cortex. These results strongly suggest that, in the mouse kidney,
glutamine synthetase is an important regulatory component of the availability of the
ammonium ions to be excreted for defending systemic acid-base balance. Furthermore, they show that, in rodents, the regulation of renal
glutamine synthetase is species-specific.