Biology of Sodium Bicarbonate Transport

描述(由申请人提供)： 项目摘要/摘要 哺乳动物的肾盆是一种袋状结构，尿液从集合管的末端流入。越来越多的证据表明，肾盆内壁的尿路上皮细胞并不是简单地发挥屏障功能，保护下层组织免受尿液pH和离子浓度的大幅变化的影响，而且可能在全身钠水平衡和血压控制方面发挥重要作用。在这方面，以前的研究已经证明，肾盆腔尿上皮介导了一种肾反射反应，其中肾盆静水压力的变化调节了肾脏钠和水的排泄和全身血压。最近，我们首次克隆了由SLC4A5基因编码的生电碳酸氢钠共转运蛋白NBC4c，该转运蛋白在哺乳动物肾脏中特异地表达于肾盆衬里的尿路上皮细胞顶膜上。最近在人类中的连锁分析研究表明SLC4A5是一个候选的高血压易感基因，这表明NBC4c在血压控制中发挥着重要但尚未确定的作用。我们推测，NBC4c在肾盆静水压改变时对肾脏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肾盆尿上皮细胞通过NBC4c的流量。在这项建议的第一部分，我们将描述参与刺激NBC4c介导的尿路上皮细胞转运的信号通路(S)的特征。在本提案的第二部分中，我们将研究关闭信号级联所涉及的路径。特别是，钙依赖的磷酸酶钙调神经磷酸酶的具体作用将被研究。这一建议将加深我们对碳酸氢钠在肾盆内共转运的生物学及其在肾脏和整个生物体钠水平衡中的重要生理作用的理解。 公共卫生相关声明 在美国，高血压是导致心脏、大脑和肾脏疾病的重要原因。最近的研究表明，NBC4是一种新的候选蛋白，与高血压有关，但其机制尚不清楚。这项提案中的研究结果将使人们更好地了解NBC4在血压控制中所起的作用，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.