Role of BK-alpha/beta 4 in renal secretion

BK-α/β 4 在肾分泌中的作用

• 批准号: 8239248
• 负责人: STEVEN SANSOM
• 金额: $ 32.3万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-20 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8239248
• 关键词: Acids; Affect; Aldosterone; Amiloride; Arrhythmia; Blood; Cell Size; Cells; Cessation of life; Complex; Data; Diet; Distal; Duct (organ) structure; Elderly; Equilibrium; Exhibits; Genes; Goals; Heart failure; In Vitro; Intake; Intercalated Cell; Ion Channel; KCNJ1 gene; Kidney; Kidney Diseases; Killer Cells; Knockout Mice; Knowledge; Laboratories; Lead; Measurement; Mechanical Stimulation; Mediating; Membrane; Methods; Mineralocorticoid Receptor; Mission; Modeling; Mus; Myocardial Infarction; Na(+)-K(+)-Exchanging ATPase; Nephrons; Patients; Pharmaceutical Preparations; Plasma; Play; Potassium; Potassium Channel; Process; Proteins; Proton-Translocating ATPases; Recycling; Renal clearance function; Reporting; Research; Research Design; Resistance; Role; Spironolactone; Staining method; Stains; Sudden Death; Testing; United States National Institutes of Health; Ventricular Arrhythmia; base; design; epithelial Na+ channel; heart function; hyperkalemia; in vivo; innovation; kidney cell; patch clamp; prevent; response; shear stress

DESCRIPTION (provided by applicant): Hyperkalemia is estimated to occur in 21% of hospitalized patients. However, the mechanism for eliminating high quantities of K during low Na intake is not known. Conventionally, it was thought to occur by direct exchange of K for Na in principal cells of the distal nephron, but when plasma [K] is high with little Na intake, K secretion must be uncoupled from Na reabsorption. Without an understanding of the K channels that mediate this process, better therapies for victims with acutely elevated plasma [K] cannot be developed. Our long-term goal is to understand the role of specific renal ion channels to eliminate K. Our focus is the large, Ca-activated K channels (BK) in the distal nephron that contain the accessory BK-b4 (BK-a/b4) in base-secreting (IC-b) and acid-secreting (IC-a) intercalated cells. The objective here, which is a critical step toward our long-goal, is to examine the role of BK-a/b4 in secreting K under high K conditions. We reported that when BK-b4 knock-out mice (b4-KO) are placed on a high K diet for 7-10 days (K adapted; KA), they exhibit increased plasma [K] and a 40% reduction in the capacity to eliminate K compare to wild type. Furthermore, high flow associated with a high K diet activates BK-a/b4, causing a release of K and cell size reduction. Thus, BK-a/b4 play a major role in how the kidney handles a high K diet; however, the mechanism by which BK-a/b4 function in this capacity is not well understood. The central hypothesis is that the elevated aldosterone of KA mice enhances K secretion by a Na-independent mechanism that utilizes K secretion by BK-a/b4 in the IC-b and K recycling by BK-a/b4 in the IC-a of the outer medullary collecting duct (OMCD). This hypothesis will be tested by pursuing three specific aims: 1. Determine whether aldosterone or high plasma K enhances BK-a/b4-mediated K secretion in KA mice. 2. Determine the role of BK-a/b4 in Na-independent K secretion. 3. Determine the roles of BK-a/b4 and KCC4 in the OMCD K recycling and flow enhancement. For these studies, we will employ methods including renal clearance measurements, patch clamping and immunohistochemical analysis of WT and b4-KO mice. The approach is innovative because we test a new model of Na-independent K secretion while isolating each potential mechanism. The proposed research is significant because it is expected to answer some long- standing questions regarding the mechanism for eliminating high quantities of K during very small amounts of Na intake. Such understanding may help prevent the large number of deaths occurring each year from treating heart failure subjects with aldosterone receptor blockers that lead to hyperkalemia-induced ventricular arrhythmias. PUBLIC HEALTH RELEVANCE: Many elderly and heart failure patients suffer fatal heart attacks because of medications that increase the potassium in the blood. These proposed studies are designed to determine how a recently discovered protein in kidney cells, called a BK-a/b4 channel, eliminates the potassium when blood potassium is elevated. The proposed research is relevant to the mission of the NIH to develop fundamental knowledge that will help to design strategies to intervene in high blood potassium-induced abnormalities in heart function.

描述（由申请方提供）：估计21%的住院患者发生高钾血症。然而，在低钠摄入期间消除大量钾的机制尚不清楚。传统上，它被认为是通过在远端肾单位的主细胞中K与Na的直接交换而发生的，但是当血浆[K]高而Na摄入少时，K分泌必须与Na重吸收解偶联。如果不了解介导这一过程的K通道，就无法为血浆[K]急性升高的患者开发更好的治疗方法。我们的长期目标是了解特定的肾离子通道在消除钾离子中的作用。我们的重点是在远端肾单位的大，钙激活的钾通道（BK），包含在碱分泌（IC-b）和酸分泌（IC-a）的插入细胞的辅助BK-b4（BK-a/b4）。这里的目标，这是我们长期目标的关键一步，是研究在高钾条件下BK-a/b4在分泌钾中的作用。我们报道，当BK-b4敲除小鼠（b4-KO）被置于高钾饮食7-10天（K适应; KA）时，与野生型相比，它们表现出血浆[K]增加和消除K的能力降低40%。此外，与高钾饮食相关的高流量激活BK-a/b4，导致K的释放和细胞尺寸减小。因此，BK-a/b4在肾脏如何处理高钾饮食中起着重要作用;然而，BK-a/b4在这种能力中发挥作用的机制还不清楚。中心假设是KA小鼠的升高的醛固酮通过Na非依赖性机制增强K分泌，该机制利用外髓集合管（OMCD）的IC-b中的BK-a/b4的K分泌和IC-a中的BK-a/b4的K再循环。这一假设将通过追求三个具体目标进行测试：1。确定是否醛固酮或高血浆K增强KA小鼠中BK-a/b4介导的K分泌。2.确定BK-a/b4在Na非依赖性K分泌中的作用。3.确定BK-a/b4和KCC 4在OMCD K再循环和流动增强中的作用。对于这些研究，我们将采用包括WT和b4-KO小鼠的肾清除率测量、膜片钳和免疫组织化学分析的方法。这种方法是创新的，因为我们测试了一种新的非钠依赖性钾分泌模型，同时分离了每种潜在的机制。这项研究意义重大，因为它有望回答一些长期存在的问题，即在摄入极少量钠的情况下消除大量钾的机制。这样的理解可能有助于防止每年因使用醛固酮受体阻滞剂治疗心力衰竭受试者导致高钾血症诱导的室性心律失常而发生的大量死亡。 公共卫生相关性：许多老年人和心力衰竭患者由于服用增加血液中钾的药物而遭受致命的心脏病发作。这些拟议的研究旨在确定最近在肾细胞中发现的一种称为BK-a/b4通道的蛋白质如何在血钾升高时消除钾。这项研究与NIH的使命相关，即开发基础知识，帮助设计干预高血钾引起的心脏功能异常的策略。