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(申请人提供)：大电导、钙激活的钾通道(BK)由形成孔道的α亚基(BK-？)组成。和辅助的β亚基(BK-？1-4)。BK高血压被多个实验室证实为BK-1亚单位(？1KO)敲除小鼠的结果，主要是肾脏对K的处理缺陷导致高钾型醛固酮增多症继发于液体滞留的结果。1.我们先前用~1KO和~4KO确定了BK-1和BK-4，它们分别定位于远端肾单位的连接小管主细胞(CNT)和间质细胞(IC)，它们具有不同的作用，使K 当动物被放入高K饮食时，分泌的Per Na被重新吸收。第一个目的是确定醛固酮和高血浆[K]在促进BK-β/β1介导的K分泌中的相对作用。第二个目的是研究BK-？/？1在钠非依赖性钾分泌中的作用。当小鼠被置于低钠饮食时，与WT相比，间接测量K分泌驱动力的经管K梯度(TTKG)显著降低？1KO。这些数据表明，BK-？/？1用于非ENaC介导的、钠非依赖性的钾分泌。我们有初步证据表明，钠非依赖性钾分泌所需的大的负跨上皮电位是？-IC细胞通过侧膜蛋白分泌HCO3和通过CFTRCl通道循环心尖部氯的结果。第三个目的是基于我们之前的研究，表明K和ATP从大脑皮层集合管的IC细胞相互依赖地运输。本研究旨在探讨BK-？/？4在IC中的作用，通过高流量诱导的ATP排泄，提高CNT和皮质集合管吸收的K/Na比值，从而局部抑制ENaC介导的Na重吸收。这些结果对于确定在医源性血浆[K]升高或挤压综合征(导致血浆[K]水平致命升高)的情况下，肾脏BK通道如何处理K将是重要的。 公共卫生相关性：由于对高血压和其他疾病进行药物治疗，患者的血钾浓度往往会变得非常高或非常低。由于血浆钾水平异常往往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清除体内钾的机制是很重要的。