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: 8725135
• 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/8725135
• 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.

描述（由申请人提供）：大电导 Ca 激活 K 通道 (BK) 由成孔 α 亚基 (BK-α) 和辅助 β 亚基 (BK-α1-4) 组成。多个实验室对敲除 BK-α1 亚基 (?1KO) 的小鼠证实，BK 高血压主要是由于肾脏处理 K 的缺陷导致液体潴留，导致高钾性醛固酮增多症。这种竞争性更新建议继续研究肾脏 BK-α/β1 的调节。我们之前用 ?1KO 和 ?4KO 确定 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，在最大化 K 值方面具有不同的作用。 当动物接受高钾饮食时，每钠重吸收所分泌的量。第一个目标确定醛固酮和高血浆 [K] 的相对作用，以增强 BK-α/β1 介导的 K 分泌。第二个目标涉及 BK-α/β1 在不依赖 Na 的 K 分泌中的作用。当小鼠接受低Na饮食时，与WT相比，α1KO的跨管钾梯度（TTKG）（钾分泌驱动力的间接测量）显着降低。这些数据表明BK-α/β1用于非ENaC介导的、不依赖Na的K分泌。我们有初步证据表明，不依赖 Na 的 K 分泌所需的大负跨上皮电位是 α-IC 细胞通过 pendrin 分泌 HCO3 以及通过 CFTR Cl 通道进行顶端 Cl 回收的结果。第三个目标基于我们之前的研究，该研究显示皮质集合管 IC 细胞中 K 和 ATP 的相互依赖运输。该目的将检查 BK-α/β4 在 IC 中的作用，通过高流量诱导的 ATP 排泄，局部抑制 ENaC 介导的 Na 重吸收，从而提高 CNT 和皮质集合管中吸收的 K 分泌与 Na 的比率。这些结果对于确定在医源性血浆 [K] 增加或挤压综合征（导致血浆 [K] 水平致命性增加）的情况下肾 BK 通道如何处理 K 非常重要。