ACID-BASE REGULATION OF RENAL METABOLISM

酸中毒时肾脏合成氨和葡萄糖的增加， 短期和长期的控制。 在短期内， 已知通过体外途径的增加的通量可以 通过某些激素，介质pH值的降低，甚至添加 酸中毒动物的血清 对酸中毒的长期反应 包括诱导某些关键酶磷酸烯醇丙酮酸 羧激酶、转氨酶和谷氨酸脱氢酶。 的诱导 磷酸烯醇丙酮酸羧激酶是已知的，由于增加的速率， 酶的合成，这与mRNA编码量的增加有关。 为了酶。 酸碱平衡的机制可以导致这种 变化未知。 本申请中描述的工作的目的是 以确定酸中毒如何影响磷酸烯醇式丙酮酸水平 肾脏中的羧激酶。 这项工作将使用老鼠和鸡 细胞内酶分布的差异和 监管模式将允许对机制进行比较。 初步工作 将表征对酸中毒的体内反应。 测定 可能参与酸中毒反应的细胞外信号将被 使用分离的近端小管细胞进行，其中， 编码磷酸烯醇式丙酮酸羧激酶的mRNA的浓度是 很容易被发现 确定了细胞外因子后， 了解其细胞内作用机制的进展。 这 将包括实验，以确定这些代理人是否通过改变 酶的转录速率。 长期目标是确定 一个共同的机制是参与酸碱介导的变化， 一些肾酶的水平。 特别是确定 在酸中毒过程中对肾脏的“信号”对于 了解肾脏代谢的调节。

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.