H/HCO3 transport in the collecting duct

描述(由申请人提供)：我们对酸碱平衡和氨代谢的理解的一个主要进展是鉴定了Rh糖蛋白是氨的转运体。在肾脏中，多条证据表明Rh糖蛋白C糖蛋白(Rhcg)在肾脏氨代谢中起着至关重要的作用。第二个进展是认识到Rhcg在主细胞中表达，而主细胞通常不参与酸碱平衡，并且主细胞Rhcg的表达与氨的排泄平行。因此，主细胞可能参与调节跨细胞氨的分泌。最后，Rhcg的表达似乎是通过转录后机制来调节的。这项应用的总体目标是确定Rhcg在酸碱平衡和钾平衡中的作用。第一个目标是确定Rhcg在肾脏对代谢性酸中毒的反应中的特殊作用。我们将使用Cre-loxP技术来产生肾脏特异性、嵌入细胞特异性和主细胞特异性Rhcg缺失的转基因小鼠。然后，我们将在对照条件下和对代谢性酸中毒的反应中检测这些小鼠的酸碱平衡，以确定Rhcg在肾脏酸碱平衡中的特定作用，以及嵌入细胞和主细胞对酸碱平衡的特定贡献。我们的第二个目标是确定Rhcg在肾脏对低钾血症的反应中的特殊作用。我们将再次使用Cre-loxP技术来产生肾脏特异性、嵌入细胞特异性和主细胞特异性Rhcg缺失的转基因小鼠。然后，我们将在对照条件下和在饮食缺钾的情况下检测这些小鼠的酸碱和钾的动态平衡，以确定Rhcg在肾脏对低钾血症的反应中的特殊作用，以及嵌入细胞和主细胞在Rhcg介导的离子转运对低钾血症的反应中的特殊贡献。 公共卫生相关性 酸碱失衡与肾结石疾病、骨质疏松症、肌肉萎缩、生长迟缓和发病率增加有关。拟议的研究将为酸碱平衡的基本机制提供新的见解，从而为新的和新的治疗方法提供基础。

DESCRIPTION (provided by applicant): A major advance in our understanding of acid-base homeostasis and ammonia metabolism is the identification that Rh glycoproteins are ammonia transporters. In the kidney, multiple lines of evidence suggest that Rh glycoprotein C Glycoprotein (Rhcg) is critically important in renal ammonia metabolism. A second advance has been the recognition that Rhcg is expressed in principal cells, a cell not generally known to be involved in acid-base homeostasis, and that principal cell Rhcg expression parallels ammonia excretion. Thus, principal cells may contribute to regulated transcellular ammonia secretion. Finally, Rhcg expression appears to be regulated through post-transcriptional mechanisms. The overall aim of this application is to determine Rhcg's role in acid-base homeostasis and in potassium homeostasis. The first goal is to determine the specific role of Rhcg in the renal response to metabolic acidosis. We will use Cre-loxP technology to generate transgenic mice with kidney-specific, intercalated cell-specific and principal cell-specific Rhcg deletion. We will then examine acid- base homeostasis in these mice under control conditions and in response to metabolic acidosis in order to determine the specific role of Rhcg in renal acid-base homeostasis, and the specific contributions of intercalated cells and principal cells to acid-base homeostasis. Our second aim is to determine Rhcg's specific role in the renal response to hypokalemia. We will again use Cre-loxP technology to generate transgenic mice with kidney- specific, intercalated cell-specific and principal cell-specific Rhcg deletion. We will then examine acid-base and potassium homeostasis in these mice under control conditions and in response to dietary potassium deficiency in order to determine the specific role of Rhcg in the renal response to hypokalemia, and the specific contributions of intercalated cells and principal cells to Rhcg-mediated ion transport in response to hypokalemia. PUBLIC HEALTH RELEVANCE Acid-base disorders are associated with renal stone disease, osteoporosis, muscle atrophy, growth retardation and increased morbidity. The proposed studies will provide new insights into the fundamental mechanisms of acid-base homeostasis, thereby providing underpinnings for new and novel treatments.