glutaminase and hippuric-acid

Hippurate (Hip), an endogenous conjugate, belongs to the group of uremic toxins. Hip stimulates P-independent glutaminase (PIG) localized at the proximal luminal membrane, desamidating glutamine with the formation of ammonia, a dominant and adaptive elimination product of H+. This appears to be important because metabolic acidosis (MAC) does not stimulate PIG. Moreover, Hip inhibits ammonia production by P-dependent mitochondrial glutaminase (PDG) that is primarily stimulated by MAC. By this mechanism, it shifts the ammonia production from mitochondria to proximal tubular lumen. MAC stimulates Hip synthesis in the liver and kidney and increases Hip plasma concentration and even fractional excretion by the kidney, which creates an effective regulatory loop of ammoniagenesis. Thus, it appears that Hip by its participation in the correction of MAC possesses the modulatory function.

Topics: Acid-Base Equilibrium; Acidosis; Ammonia; Animals; Glutaminase; Hippurates; Humans; Kidney; Kidney Failure, Chronic; Liver; Rats; Toxins, Biological; Uremia

The key regulatory enzymes of kidney ammoniagenesis appear to be P-dependent (PDG) and P-independent (PIG) glutaminases. While the participation of PDG has been satisfactorily elucidated, the significance of PIG remains doubtful. Rat kidney cortex slices synthesized ammonia even under basal conditions. Metabolic acidosis, hippurate and insulin stimulated ammonia production. Under basal conditions, PDG activity in kidney homogenate, was twice as high as PIG activity. Metabolic acidosis stimulated ammonia production by the stimulation of both PDG (100%) and PIG (57%) activities. Hippurate stimulated only PIG activity both under basal conditions (90%) and in metabolic acidosis (52%), while it inhibited PDG activity only insignificantly under basal conditions and markedly (53%) in metabolic acidosis. Insulin stimulated both PIG and PDG activities under basal conditions as well as in metabolic acidosis and potentiated the PIG stimulation by hippurate while it potentiated the hippurate inhibition of PDG both under basal conditions and in acidotic rats. In conclusion, both PDG and PIG participate in ammoniagenesis and are stimulated by metabolic acidosis and insulin. Hippurate stimulates PIG, while it inhibits PDG in metabolic acidosis and even after insulin administration. The effect of hippurate appears to be of physiological interest.

Topics: Acidosis; Ammonia; Animals; Glutaminase; Hippurates; Insulin; Kidney; Kidney Cortex; Male; Rats; Rats, Wistar