ACID-BASE REGULATION OF RENAL METABOLISM

酸中毒时肾脏对氨和葡萄糖的合成增加 既有短期控制，也有长期控制。在短期内， 已知通过体外途径的增加的通量可以带来 大约是由于某些激素，介质pH的降低，甚至是添加 一种酸性动物的血清。对酸中毒的长期反应 涉及某些关键酶的诱导，磷酸烯醇式丙酮酸 羧酸激酶、谷氨酰胺酶和谷氨酸脱氢酶。的归纳 已知的是，磷酸烯醇式丙酮酸羧酸激酶是由于 酶的合成，这与mRNA编码量的增加有关 为了这种酶。酸碱平衡导致这种情况的机制 变化是未知的。本申请中描述的工作的目的是 确定酸中毒如何影响磷烯醇式丙酮酸水平 肾脏中的羧酸激酶。这项工作将同时使用老鼠和鸡 其中细胞内酶分布的差异和不同 监管模式将允许对机制进行比较。最初的工作 将表征体内对酸中毒的反应。的决定 可能参与酸中毒反应的细胞外信号将是 编码磷酸烯醇式丙酮酸羧激酶的mRNA浓度为 容易察觉的。在确定了胞外因子之后，这项工作将 了解其细胞内作用机制的进展。这 将包括实验，以确定这些代理是否通过改变 酶的转录速率。长期目标是确定是否 一种共同的机制涉及到酸-碱介导的细胞周期变化。 一些肾脏酶的水平。尤其是识别出 酸中毒时对肾脏的“信号”对

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.