Role of BK-alpha 1 in flow-dependent K secretion in the CNT

BK-alpha 1 在 CNT 中流依赖性 K 分泌中的作用

• 批准号: 8368587
• 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: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8368587
• 关键词: Address; Aldosterone; Amiloride; Animals; Apical; Arrhythmia; Bicarbonates; Cations; Cell Line; Cells; Chemicals; Crush syndrome; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Diet; Distal; Duct (organ) structure; Excretory function; Exhibits; Failure; Hyperaldosteronism; Hypertension; Intake; Intercalated Cell; KCNJ1 gene; Kidney; Laboratory mice; Lead; Liquid substance; Measurement; Mediating; Medical; Mus; Nephrons; Patients; Pharmacological Treatment; Plasma; Potassium; Potassium Channel; Production; Property; Proteins; Recycling; Regulation; Relative (related person); Role; Secondary to; Sudden Death; Testing; Tissues; base; design; driving force; epithelial Na+ channel; feeding; large-conductance calcium-activated potassium channels; patch clamp; response

DESCRIPTION (provided by applicant): Large conductance, Ca-activated K channels (BK) are comprised of a pore-forming alpha subunit (BK-?) and an ancillary beta subunit (BK-?1-4). BK hypertension, demonstrated by several laboratories for mice with knock-outs of the BK-?1 subunit (?1KO), is mostly the result of fluid retention secondary to defective renal handling of K resulting in hyperkalemic aldosteronism. This competitive renewal proposes to continue studies of the regulation of the renal BK-?/?1. We previously determined with ?1KO and ?4KO that BK-?/?1 and BK-?/?4, which are localized in the connecting tubule principal cells (CNT) and intercalated cells (IC), respectively, of the distal nephron, have distinct roles to maximize the K secreted per Na reabsorbed when animals are placed on a high K diet. The first Aim determines the relative roles of aldosterone and high plasma [K] to enhance BK-?/?1 mediated K secretion. The second Aim addresses the role of BK-?/?1 in Na-independent K secretion. When mice are placed on a low Na diet, the transtubular K gradient (TTKG), an indirect measurement of the driving force for K secretion, is significantly reduced for ?1KO, compared with WT. These data indicate that the BK-?/?1 is used for non-ENaC-mediated, Na-independent K secretion. We have preliminary evidence that the large negative transepithelial potential required for Na-independent K secretion is the result of ?-IC cell HCO3 secretion via pendrin in conjunction with apical Cl recycling via CFTR Cl channels. The third Aim is based on our previous study showing co-dependent transport of K and ATP from IC cells of the cortical collecting duct. This Aim will examine the role of the BK-?/?4 in IC to enhance the ratio of K secreted to Na absorbed in the CNT and cortical collecting ducts by the high flow-induced excretion of ATP, which locally inhibits ENaC-mediated Na reabsorption. These results will be important for determining how K is handled by renal BK channels in conditions of iatrogenic increases in plasma [K] or with crush syndrome, which causes fatal increases in plasma [K] levels. PUBLIC HEALTH RELEVANCE: As a consequence of pharmacological treatment for high blood pressure and other medical conditions, plasma K concentrations often become very high or very low in patients. Because abnormal levels of plasma K often lead to cardiac arrhythmias and sudden death, it is important to understand the mechanisms by which chemicals regulate the kidney proteins that eliminate K from the body.

描述（由申请人提供）：大电导钙激活钾通道（BK）由成孔α亚基（BK-？）和辅助β亚单位（BK-？第1-4段）。BK高血压，证明了几个实验室的小鼠与BK-？1亚基（？1 KO），主要是继发于K的肾处理缺陷导致高钾性醛固酮增多症的液体潴留的结果。这一竞争性更新建议继续研究肾脏BK-？/？1.我们之前确定的？1 KO和？4KO那个BK-？/？1和BK-？/？4分别位于远端肾单位的连接小管主细胞（CNT）和闰细胞（IC）中，具有不同的作用，以最大化K 当动物被置于高钾饮食时，分泌的每钠重吸收。第一个目的是确定醛固酮和高血浆[K]的相对作用，以提高BK-？/？1介导K分泌。第二个目标是解决BK-？/？1.非钠依赖性钾分泌。当小鼠被放置在一个低钠饮食，经前庭钾梯度（TTKG），钾分泌的驱动力的间接测量，显着减少？1 KO，与WT相比。这些数据表明，BK-？/？1用于非ENaC介导的Na非依赖性K分泌。我们有初步证据表明，钠非依赖性钾分泌所需的大负跨上皮电位是？IC细胞HCO 3分泌通过pendrin与顶端Cl再循环通过CFTR Cl通道。第三个目的是基于我们以前的研究，显示了K和ATP从皮质集合管IC细胞的共依赖转运。本目标将研究BK-？/？4在IC中，通过高流量诱导的ATP排泄，提高CNT和皮质收集管中分泌的K与吸收的Na的比率，这局部抑制ENaC介导的Na重吸收。这些结果对于确定在血浆[K]医源性增加或挤压综合征（导致血浆[K]水平致命性增加）条件下肾BK通道如何处理K具有重要意义。 公共卫生相关性：由于高血压和其他医学病症的药物治疗，患者的血浆K浓度通常变得非常高或非常低。由于血浆钾水平异常通常会导致心律失常和猝死，因此了解化学物质调节肾脏蛋白质以消除体内钾的机制非常重要。