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: 8897344
• 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 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8897344
• 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-α) and an ancillary beta subunit (BK-ß1-4). BK hypertension, demonstrated by several laboratories for mice with knock-outs of the BK-ß1 subunit (ß1KO), 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-α/ß1. We previously determined with ß1KO and ß4KO that BK-α/ß1 and BK-α/ß4, 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-α/ß1 mediated K secretion. The second Aim addresses the role of BK-α/ß1 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 ß1KO, compared with WT. These data indicate that the BK-α/ß1 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 ß-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-α/ß4 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-ß1-4) 组成，由 BK 高血压证明。一些实验室对敲除 BK-ß1 亚基 (ß1KO) 的小鼠进行研究，这主要是由于 K 的肾脏处理缺陷继发的液体潴留的结果，导致这种竞争性更新建议继续研究肾 BK-α/ß1 的调节，我们之前使用 ß1KO 和 ß4KO 发现 BK-α/ß1 和 BK-α/ß4，它们位于连接小管主细胞中。远端肾单位的 (CNT) 和闰细胞 (IC) 分别在最大化 K 值方面具有不同的作用 当动物采用高钾饮食时，每钠重吸收的分泌量 第一个目标确定醛固酮和高血浆 [K] 在增强 BK-α/ß1 介导的钾分泌方面的相对作用。 /ß1 影响不依赖 Na 的 K 分泌。当小鼠接受低 Na 饮食时，跨管 K 梯度 (TTKG)（K 分泌驱动力的间接测量）显着降低。 ß1KO，与 WT 相比，这些数据表明 BK-α/ß1 用于非 ENaC 介导的、不依赖 Na 的 K 分泌。 ß-IC 细胞通过 pendrin 分泌 HCO3 并通过 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，显示了相互依赖的转运。来自皮质集合管 IC 细胞的 K 和 ATP 该目的将检查 BK-α/ß4 在 IC 中的作用，以提高高流量诱导的 CNT 和皮质集合管中分泌的 K 与吸收的 Na 的比率。 ATP 的排泄，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] 增加或挤压综合征的情况下肾脏 BK 通道如何处理 K 非常重要。导致血浆 [K] 水平致命性升高。

项目成果

BK channels and a new form of hypertension.

BK 通道和一种新形式的高血压。

• DOI: 10.1038/ki.2010.272
• 发表时间: 2010-11
• 期刊: Kidney international
• 影响因子: 19.6
• 作者: Grimm, P. Richard;Sansom, Steven C.
• 通讯作者: Sansom, Steven C.

Proton MR Spectroscopy Measurements of White and Brown Adipose Tissue in Healthy Humans: Relaxation Parameters and Unsaturated Fatty Acids.

健康人体白色和棕色脂肪组织的质子磁共振波谱测量：松弛参数和不饱和脂肪酸。

• DOI: 10.1148/radiol.2021202676
• 发表时间: 2021-03-16
• 期刊: Radiology
• 影响因子: 19.7
• 作者: R. Ouwerkerk;A. Hamimi;J. Matta;Khaled Z. Abd;J. Eary;Zahraa Abdul Sater;Kong Y. Chen;A. Cypess;A. Gharib
• 通讯作者: A. Gharib

Quantification of the Capacity for Cold-Induced Thermogenesis in Young Men With and Without Obesity.

肥胖和不肥胖的年轻男性冷诱导生热能力的量化。

• 发表时间: 2019
• 作者: Brychta, Robert J;Huang, Shan;Wang, Juan;Leitner, Brooks P;Hattenbach, Jacob D;Bell, Sarah L;Fletcher, Laura A;Perron Wood, Rachel;Idelson, Christopher R;Duckworth, Courtney J;McGehee, Suzanne;Courville, Amber B;Bernstein, Shanna B;Reitman, M
• 通讯作者: Reitman, M

Deficient acid handling with distal RTA in the NBCe2 knockout mouse.

NBCe2 敲除小鼠远端 RTA 处理酸不足。

• DOI: 10.1152/ajprenal.00163.2015
• 发表时间: 2015-09-15
• 期刊: American journal of physiology. Renal physiology
• 作者: Donghai Wen;Yang Yuan;Ryan J. Cornelius;Huaqing Li;Paige Warner;Bangchen Wang;Jun Wang‐France;T. Boettger;S. Sansom
• 通讯作者: S. Sansom

Predicting Body Composition From Anthropometrics.

从人体测量学预测身体成分。

• 发表时间: 2021-11
• 作者: Chen; Kong Y
• 通讯作者: Kong Y