Glutamine synthetase (GS) catalyzes the recycling of NH4+ with glutamate to form glutamine. Glutamine synthetase is highly expressed in the renal proximal tubule, suggesting ammonia recycling via glutamine synthetase could decrease net ammoniagenesis and thereby limit ammonia available for net acid excretion. This study's purpose was to determine the role of proximal tubule glutamine synthetase in ammonia metabolism under basal conditions and during metabolic acidosis. We generated mice with proximal tubule-specific glutamine synthetase deletion (PT-GS-KO) using Cre-loxP techniques. Under basal conditions, PT-GS-KO increased urinary ammonia excretion significantly. Increased ammonia excretion occurred despite decreased expression of key proteins involved in renal ammonia generation. Following induction of metabolic acidosis the ability to increase ammonia excretion was impaired significantly by PT-GS-KO. The blunted increase in ammonia excretion occurred despite greater expression of multiple components of ammonia generation, including SN1, phosphate-dependent glutaminase, phosphoenolpyruvate carboxykinase, and sodium-coupled electrogenic bicarbonate cotransporter (NBCe1). We conclude: 1) glutamine synthetase-mediated ammonia recycling in the proximal tubule contributes to both basal and acidosis-stimulated ammonia metabolism; and, 2) adaptive changes in other proteins involved in ammonia metabolism occur in response to PT-GS-KO and cause an underestimation of the role of proximal tubule glutamine synthetase expression.
- glutamine synthetase
- proximal tubule
- Copyright © 2015, American Journal of Physiology - Renal Physiology