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，ca激活的K通道（BK）由成孔α亚基（BK- 1）和辅助β亚基（BK- 1-4）组成。BK-?基因被敲除的小鼠，几个实验室证明了BK-？1亚基(？1KO)，主要是继发于肾处理钾缺陷导致高钾血症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的调控。我们之前确定了？1KO和？4KO那BK-?/？1和BK-?/？4，它们分别位于远端肾元的连接小管主细胞（CNT）和插层细胞（IC）中，对K的最大化有不同的作用