ACID-BASE REGULATION OF RENAL METABOLISM

在酸中毒中，肾脏对氨和葡萄糖的合成增加

The increased synthesis of ammonia and glucose by the kidney in acidosis is regulated by both short-term and long-term controls. In the short-term it is known that increased flux through the pathway in vitro can be brought about by certain hormones, a decrease in the medium pH or even the addition of serum from an acidotic animal. The long-term response to acidosis involves induction of certain key enzymes, phosphoenolpyruvate carboxykinase, glutaminase and glutamate dehydrogenase. The induction of phosphoenolpyruvate carboxykinase is known to be due to increased rates of enzyme synthesis and this correlates with increased amounts of mRNA coding for the enzyme. The mechanism by which acid-base balance can cause such changes is unknown. The aim of the work described in this application is to determine how acidosis can influence the levels of phosphoenolpyruvate carboxykinase in the kidney. The work will use both rats and chickens where differences in intracellular enzyme distribution and different regulatory patterns will allow comparison of mechanisms. The initial work will characterize the in vivo response to acidosis. Determination of extracellular signals possibly involved in the acidosis response will be carried out using isolated proximal tubule cells where changes in the concentrations of mRNA coding for phosphoenolpyruvate carboxykinase are readily detectable. Having identified extracellular agents the work will progress to understanding their intracellular mechanism of action. This will include experiments to determine if these agents act by changing transcription rates for the enzyme. The long-term goal is to determine if a common mechanism is involved in the acid-base mediated changes in the levels of a number of renal enzymes. In particular the identification of the "signal" to the kidney during acidosis is of fundamental importance to the understanding of the regulation of renal metabolism.