H/HCO3 transport in the collecting duct

描述(申请人提供)：我们对关键肾功能了解的一个主要进展是最近认识到谷氨酰胺合成酶可能在肾脏电解质和氮代谢中起关键作用。谷氨酰胺合成酶介导NH4+和谷氨酸转化为谷氨酰胺，从而“不生成”氨并“再生”有用的氨基酸--谷氨酰胺。谷氨酰胺合成酶在肾脏的多种不同类型的细胞中表达，包括参与氨生成的细胞(近端小管)。 以及那些传统上被认为只参与氨运输的细胞(嵌入细胞)。谷氨酰胺合成酶在这些细胞类型中的存在，以及我们的初步数据表明，它在多种条件下的调节表明了调节肾脏氨代谢和氮平衡的新机制。这项应用的总体目标是确定谷氨酰胺合成酶在肾脏不同主要细胞类型中的作用，在这些细胞中，谷氨酰胺合成酶在肾脏的氨代谢、酸碱代谢、钾代谢和氮代谢中表达。第一个目标是确定谷氨酰胺合成酶在近端小管中表达的特定作用。我们将使用Cre-loxP技术产生近端小管特异性谷氨酰胺合成酶缺失的小鼠，以确定近端小管谷氨酰胺合成酶在正常酸碱平衡中的作用，以及在代谢性酸中毒、低钾血症和饮食蛋白限制的肾脏反应中的作用。我们的第二个目标是确定谷氨酰胺合成酶在嵌入细胞中的表达的特殊作用。我们将使用Cre-loxP技术来产生插入细胞特异性谷氨酰胺合成酶缺失的小鼠。我们将利用这些小鼠来确定插层细胞谷氨酰胺合成酶在正常酸碱平衡中的作用，以及在代谢性酸中毒、低钾血症和饮食蛋白限制的肾脏反应中的作用。

DESCRIPTION (provided by applicant): A major advance in our understanding of key renal function is the recent recognition that the enzyme glutamine synthetase may mediate critical roles in renal electrolyte and nitrogen metabolism. Glutamine synthetase mediates the conversion of NH4+ and glutamate into glutamine, thereby "ungenerating" ammonia and "regenerating" the useful amino acid glutamine. Glutamine synthetase is expressed in multiple distinct cell types in the kidney, including cells involved in ammonia generation (proximal tubule) and those traditionally thought to be involved solely in ammonia transport (intercalated cells). The presence of glutamine synthetase in these cell types, and our preliminary data identifying its regulation in multiple conditions suggests novel and new mechanisms regulating renal ammonia metabolism and in the regulation of nitrogen balance. The overall aim of this application is to determine the roles of glutamine synthetase in the different major cell types in the kidney in which it is expressed in renal ammonia, acid-base, potassium and nitrogen metabolism. The first goal is to determine the specific role of glutamine synthetase expression in the proximal tubule. We will use Cre-loxP technology to generate mice with proximal tubule-specific glutamine synthetase deletion, which we will use to determine the role of proximal tubule glutamine synthetase in normal acid-base homeostasis, and in the renal response to metabolic acidosis, hypokalemia and dietary protein restriction. Our second aim is to determine the specific role of glutamine synthetase expression in intercalated cells. We will use Cre-loxP technology to generate mice with intercalated cell-specific glutamine synthetase deletion. We will use these mice to determine the role of intercalated cell glutamine synthetase in normal acid- base homeostasis, and in the renal response to metabolic acidosis, hypokalemia and dietary protein restriction.