glutaminase and Uremia

Topics: Animals; Chickens; Glutamate-Ammonia Ligase; Glutamates; Glutaminase; Glutamine; Glycine; Humans; Hypoxanthines; Inosine; Inosine Nucleotides; Liver; Nitrogen; Nucleotidases; Phosphorylase Kinase; Rats; Serine; Uremia; Uric Acid; Xanthine Oxidase; Xanthines

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 effects of chronic uraemia on glucose production and nitrogen release (urea plus ammonia formation) from alanine, glutamine or serine in isolated rat hepatocytes were studied. Uraemia increased the rate of formation of urea plus ammonia from all three amino acids by 38-93% when they were present at a final concentration of 10 mmol/l. At lower concentrations (2 mmol/l) the rate of nitrogen release was not significantly increased. Hepatocytes from normal rats whose food intake had been restricted to the level of that of uraemic rats did not show the increased rates of nitrogen release. The increased rates of nitrogen release with hepatocytes from uraemic rats were not accompanied by increased rates of glucose synthesis. Instead, accumulation of metabolic intermediates occurred: lactate and pyruvate (alanine or serine as substrates) and glutamate (glutamine as substrate). Livers of uraemic rats had increased activities of glutaminase (30%) and serine dehydratase (100%). Hepatocytes from normal rats treated with phlorhizin to increase the plasma glucagon/insulin ratio behaved in a similar manner to hepatocytes from uraemic rats. They had increased serine dehydratase activity, and increased rates of utilization of serine or glutamine. The possible implications of these findings for human uraemia are discussed.

Topics: Acidosis; Alanine; Amino Acids; Ammonia; Animals; Gluconeogenesis; Glutaminase; Glutamine; In Vitro Techniques; L-Serine Dehydratase; Liver; Male; Phlorhizin; Rats; Rats, Inbred Strains; Serine; Urea; Uremia

Topics: Animals; Brain Chemistry; Glutaminase; Glutamine; Male; Nephrectomy; Rats; Uremia