Role of BK-alpha/beta 4 in renal secretion

BK-α/β 4 在肾分泌中的作用

• 批准号: 8541844
• 负责人: STEVEN SANSOM
• 金额: $ 31.17万
• 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/8541844
• 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.

描述（由申请人提供）：估计 21% 的住院患者会出现高钾血症。然而，在低钠摄入期间消除大量钾的机制尚不清楚。传统上，人们认为这是通过远端肾单位主细胞中 K 与 Na 的直接交换而发生的，但当血浆 [K] 高而 Na 摄入量很少时，K 分泌必须与 Na 重吸收脱钩。如果不了解介导这一过程的 K 通道，就无法为血浆 [K] 急剧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肾离子通道消除 K 的作用。我们的重点是远端肾单位中大型 Ca 激活 K 通道 (BK)，其在碱分泌 (IC-b) 和酸分泌 (IC-a) 嵌入细胞中包含辅助 BK-b4 (BK-a/b4)。这里的目标是检查 BK-a/b4 在高 K 条件下分泌 K 的作用，这是实现我们长期目标的关键一步。我们报道，当 BK-b4 敲除小鼠 (b4-KO) 接受高 K 饮食 7-10 天（K 适应；KA）时，与野生型相比，它们的血浆 [K] 增加，消除 K 的能力降低 40%。此外，与高钾饮食相关的高流量会激活 BK-a/b4，导致钾的释放和细胞尺寸的减小。因此，BK-a/b4 在肾脏如何处理高钾饮食方面发挥着重要作用；然而，BK-a/b4 发挥这种作用的机制尚不清楚。中心假设是，KA 小鼠醛固酮升高通过 Na 独立机制增强 K 分泌，该机制利用 IC-b 中 BK-a/b4 的 K 分泌和外髓集合管 (OMCD) IC-a 中 BK-a/b4 的 K 回收。该假设将通过追求三个具体目标进行检验： 1. 确定醛固酮或高血浆 K 是否会增强 KA 小鼠中 BK-a/b4 介导的 K 分泌。 2. 确定 BK-a/b4 在不依赖 Na 的 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率测量、膜片钳和 WT 和 b4-KO 小鼠免疫组织化学分析在内的方法。该方法具有创新性，因为我们测试了一种不依赖于 Na 的 K 分泌的新模型，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。这种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而导致大量死亡，醛固酮受体阻滞剂会导致高钾血症诱发的室性心律失常。