Gamma glutamyltransferase contribution to renal ammoniagenesis in vivo.
The role of gamma-glutamyltransferase (gamma-GT) in renal ammoniagenesis and glutamine utilization was evaluated in the intact functioning rat kidney. Total NH4+ released, as the sum of renal venous and urinary NH4+, was measured under conditions of chronic metabolic acidosis and paraminohippurate infusion. Ammonia derived from extracellular gamma-GT hydrolysis of glutamine was differentiated from that produced by intracellular phosphate dependent glutaminase (PDG) by employing acivicin, a gamma-GT inhibitor. In non-acidotic animals acivicin administration inhibited gamma-GT 95% and renal venous NH4+ release 48%; NH4+ release into the urine was not inhibited. Chronic metabolic acidosis elevated total NH4+ release 2.5fold, associated with adaptive increase in both gamma-GT and PDG; acivicin reduced total NH4+ released 36% with both renal venous and urinary release effected. The contribution of gamma-GT to total NH4+ production doubles in metabolic acidosis in agreement with the adaptive rise in the in vitro assayed gamma-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; gamma-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 NH4+ release due entirely to enhanced NH4+ 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 gamma-GT and glutamine hydrolysis.
D000641:Ammonia / Q000032:analysis / Q000096:biosynthesis*; D000818:Animals; D005973:Glutamine / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology; D007668:Kidney / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D051381:Rats; D011919:Rats, Inbred Strains; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors / Q000502:physiology*; D010130:p-Aminohippuric Acid / Q000494:pharmacology
D007555:Isoxazoles; D005973:Glutamine; D000641:Ammonia; D005723:gamma-Glutamyltransferase; C006303:acivicin; D010130:p-Aminohippuric Acid