Glutamine metabolism in metabolic acidosis

In chronic metabolic acidosis in the rat, there is increased ammoniagenesis, gluconeogenesis and renal extraction of gluatmine with induction of renal phosphate-dependent glutaninase (PDG). Because the stimulus for these changes is not yet clear and also because acute acidosis is the more common clinical problem, the present study deals mainly with the metabolism of glutamine in acute metabolic acidosis. When acute metabolic acidosis is produced in rats by administration of mineral acid or by causing them to swim, thus inducing a severe lactic acidosis, a factor is found in the plasma which stimulates renal glutamine uptake and ammoniagenesis in vivo as well as in vitro. Acute acidosis dose not induce synthesis of PDG in the kidney but causes a change in enzyme kinetics. The plasma factor not only enhances glutamine entry into cells, but apparently causes a conformational change in PDG, as shown by an increase in V1.0mM/Vmax. Intestinal metabolism of glutamine is also stimulated in vivo and in vitro by the plasma factor of acute acidosis. (AU)

Renal transport and metabolism of glutamine

The experiments described in this thesis were designed to investigate the mechanism of glutamine transport and the effect of acute acidosis on glutamine transport and metabolism in the rat kidney. The experiments done with kidney slices investigated the effect of several amino acids chosen from different structural groups on uptake of glutamine. Proline (an ammino acid) and glycine (at inhibitory concentrations) were found to inhibit ammonia production and glutamine uptake significantly. When a sodium free incubation buffer was used the inhibitory effect of proline and glycine on glutamine uptake disappeared, indicating that the inhibition by proline was sodium dependent. In similar experiments with isolated kidney proximal tubules in a sodium containing buffer, proline also caused a decrease in glutamine uptake and ammonia production. Intracellular/extracellular glutamine distributions ratios in tubules however, showed a marked increase in the presence of proline. The explanation for this is not that proline shares a transport site with glutamine but rather that it is metabolised to glutamate which causes an inhibition of phosphate dependent glutaminase and hence decreased glutamine utilisation. This decreased utilisation leads to an accumulation of glutamine within the renal cell and subsequently increased intracellular/extracellular glutamine distribution ratios. The inhibitory effect of proline on glutamine uptake was much less in experiments with kidney slices from chronically acidotic rats. Isolated tubules from acutely acidotic rats showed increased intracellular/extracellular glutamine distribution ratios, increased ammonia production and glutamine uptake in tubules. When tubules from normal rats were incubated in sera from acutely acidotic rats there was a similar increase in intracellular/extracellular glutamine distribution ratios, ammonia production and glutamine uptake. The effect of the serum however, was not due to the accumulation of glutamate because glutamate levels in tubules were unchanged after incubation in sera from the acutely acidotic rats (AU)

Microscopic and enzyme histochemical studies on the liver and kidney of rats treated with fulvine, the toxic alkaloidal constituent of crotalaria fulva

Histochemical changes in the liver of rats, treated with the pyrrolizidine alkaloidal constituent of Crotalaria fulva, indicated primarily damage of the hepatic parenchymal cells. The observed differences in activity of enzymes suggested functional inpairment of the cell membrane, mitochondria, endoplasmatic reticulum, and lysosomes in the liver cells. In large doses, fulvine produced a hyaline droplet degeneration in the epithelium of the proximal convoluted tubules of the kidney. Stability of the mitochondrial and changes in activity of the lysosomal enzymes would imply a functional adaptation, rather than primary damage of the epithelium.(AU)