Gamma glutamyltransferase contribution to renal ammoniagenesis in vivo

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Abstract
The·role of γ-glutamyltransferase (γ-GT) in renal ammoniagenesis and glutamine utilization was evaluated in the intact functioning rat kidney. Total NH +4 released, as the sum of renal venous and urinary NH +4 , was measured under conditions of chronic mebolic acidosis and paraminohippurate infusion. Ammonia derived from extracellular γ-GT hydrolysis of glutamine was differentiated from that produced by intracellular phosphate dependent glutaminase (PDG) by employing acivicin, a γ-GT inhibitor. In nonacidotic animals acivicin administration inhibited γ-GT 95% and renal venous NH +4 release 48%; NH +4 release into the urine was not inhibited. Chronic metabolic acidosis elevated total NH +4 release 2.5fold, associated with adaptive increase in both γ-GT and PDG; acivicin reduced total NH +4 released 36% with both renal venous and urinary release effected. The contribution of γ-GT to total NH +4 production doubles in metabolic acidosis in agreement with the adaptive rise in the in vitro assayed γ-GT activity. Luminal ammoniagenesis increases in chronic acidosis associated with a fall in urinary glutamine concentration and a rise in the blood to urine glutamine concentration gradient; γ-GT inhibition eliminates this gradient suggesting luminal ammoniagenesis is largely dependent upon the paracellular glutamine flux. In support of this, paraminohippurate (PAH) infusion increased total renal NH +4 release due entirely to enhanced NH +4 excretion. PAH stimulated luminal ammoniagenesis was associated with an acceleration of renal glutamine extraction and a steeper blood to urine glutamine diffusion gradient; acivicin blocked this response consistent with PAH secretion coupled to activation of intraluminal γ-GT and glutamine hydrolysis.