Biology of Sodium Bicarbonate Transport

描述（由申请人提供）： 项目总结/摘要 哺乳动物的肾盂是囊状结构，尿液从收集管的末端部分流入其中。越来越多的证据表明，肾盂内衬的尿路上皮细胞不仅在保护下面的组织免受尿液pH和离子浓度的巨大变化方面发挥屏障功能，而且可能在全身钠和水平衡以及血压控制中发挥重要作用。在这方面，先前的研究已经证明，肾盂尿路上皮介导肾肾反射反应，其中肾盂静水压力的变化调节肾钠和水排泄以及全身血压。最近，我们已经证明，产电碳酸氢钠协同转运蛋白，NBC 4c，首先在我们的实验室克隆和SLC 4A 5基因编码的是专门表达在哺乳动物肾脏上的肾盂衬里的泌尿上皮细胞的顶膜。最近的人类连锁分析研究表明SLC 4A 5是一个候选的高血压易感基因，这表明NBC 4c在血压控制中具有重要但尚未表征的作用。我们假设NBC 4c在响应肾盂静水压力变化的肾钠和水排泄的反射调节中起关键作用。在初步实验中，静水压力的增加刺激了通过NBC 4c在肾盂尿路上皮细胞中的通量。在本提案的第一部分中，我们将表征参与刺激NBC 4c介导的尿路上皮细胞转运的信号通路。在这个建议的第二部分，我们将研究参与关闭信号级联的途径。特别是，钙依赖性磷酸酶钙调神经磷酸酶的具体作用将进行研究。这一建议将提高我们对肾盂中碳酸氢钠共转运的生物学及其在肾脏和整个生物体中钠和水稳态中的重要生理作用的理解。 公共卫生相关性声明 高血压（高血压）是美国心脏、大脑和肾脏疾病的重要原因。最近的研究表明NBC 4是一种与高血压相关的新的候选蛋白，但其机制完全未知。该提案中的研究结果将导致对NBC 4在血压控制中所起作用的更多理解，并可能导致治疗高血压的重要新方法。

DESCRIPTION (provided by applicant): Project Summary/Abstract The mammalian renal pelvis is a pouch-like structure into which urine flows from the terminal portions of the collecting ducts. There is increasing evidence that the uroepithelial cells lining the renal pelvis do not simply perform a barrier function in protecting the underlying tissue from large changes in urinary pH and ion concentration but may play an important role in whole body sodium and water balance, and blood pressure control. In this regard, previous studies have demonstrated that the renal pelvic uroepithelium mediates a renorenal reflex response wherein changes in renal pelvic hydrostatic pressure modulate renal sodium and water excretion and systemic blood pressure. Recently we have demonstrated that the electrogenic sodium bicarbonate cotransporter, NBC4c, first cloned in our laboratory and encoded by the SLC4A5 gene is specifically expressed in the mammalian kidney on the apical membrane of uroepithelial cells lining the renal pelvis. Recent linkage analysis studies in humans have implicated SLC4A5 as a candidate hypertension- susceptibility gene, suggesting an important and as yet uncharacterized role for NBC4c in blood pressure control. We hypothesized that NBC4c plays a key role in the reflex modulation of renal sodium and water excretion in response to changes in renal pelvic hydrostatic pressure. In preliminary experiments, an increase in hydrostatic pressure stimulated the flux through NBC4c in renal pelvic uroepithelial cells. In this first part of this proposal, we will characterize the signaling pathway(s) involved in the stimulation of NBC4c-mediated transport in uroepithelial cells. In the second part of this proposal, we will study the pathways involved in switching off the signaling cascade. In particular, the specific role of the calcium-dependent phosphatase calcineurin will be studied. This proposal will enhance our understanding of the biology of sodium bicarbonate cotransport in the renal pelvis and its important physiological role in sodium and water homeostasis in the kidney and whole organism. Public Health Relevance Statement High blood pressure (hypertension) is an important cause of heart, brain and kidney disease in the United States. Recent studies have implicated NBC4 as a new candidate protein that is associated with high blood pressure however the mechanism is entirely unknown. The results of the studies in this proposal will lead to an increased understanding of the role that NBC4 plays in blood pressure control and potentially lead to important new approaches for treating high blood pressure.