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（由申请人提供）：估计高钾血症发生在21％的住院患者中。但是，尚不清楚消除低Na摄入过程中消除大量K的机制。通常，人们认为它是通过远端肾源的主要细胞直接交换为Na的K发生的，但是当血浆[K]较高而Na摄入量很小时，必须将K分泌与Na的重吸收取消偶联。在不了解介导此过程的K通道的情况下，无法开发出对血浆急性升高的受害者的更好疗法[K]。我们的长期目标是了解特定肾离子通道消除K的作用。我们的重点是远端肾单位中包含辅助BK-B4（BK-A/B4）在基础分泌（IC-B）（IC-B）和分泌酸（IC-A）中的大型CA激活K通道（BK）。这里的目标是迈向我们长期目标的关键一步，是检查BK-A/B4在高k条件下分泌K的作用。我们报道说，当BK-B4敲除小鼠（B4-KO）放在高k饮食上7-10天（k适应; ka）时，它们表现出增加的血浆[K] [K]，而消除K与野生型相比，消除K的能力降低了40％。此外，与高k饮食相关的高流量会激活BK-A/B4，从而释放K和细胞尺寸减少。因此，BK-A/B4在肾脏如何处理高K饮食方面起着重要作用。但是，BK-A/B4以这种能力功能的机制尚不清楚。中心假设是，Ka小鼠的醛固酮升高通过NA独立的机制增强K分泌，该机制利用BK-A/B4在IC-B中通过BK-A/B4分泌K，而BK-A/B4在髓外收集管（OMCD）的IC-A中通过BK-A/B4进行了k回收。该假设将通过追求三个特定目的来检验：1。确定醛固酮还是高血浆K是否可以增强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KCC4在OMCD K回收和流动增强中的作用。对于这些研究，我们将采用包括肾清除测量，贴片夹紧和WT和B4-KO小鼠的免疫组织化学分析的方法。该方法具有创新性，因为我们在隔离每个潜在机制的同时测试了独立K分泌的新模型。拟议的研究很重要，因为预计它将回答有关在少量NA摄入量中消除大量K的机制的一些长期问题。这种理解可能有助于防止每年通过使用醛固酮受体阻滞剂治疗心力衰竭受试者的大量死亡，从而导致高钾血症引起的心室心律失常。 公共卫生相关性：许多老年人和心力衰竭患者因增加血液中钾的药物而遭受致命的心脏病发作。这些提出的研究旨在确定肾细胞中最近发现的蛋白质如何在升高血钾时消除钾。拟议的研究与NIH的使命涉及开发基本知识的使命，该知识将有助于设计策略以干预高钾引起的心脏功能异常。