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

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

• DOI: 10.1152/ajprenal.00163.2015
• 发表时间: 2015-09
• 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

Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans.

• DOI: 10.1016/j.cmet.2013.12.017
• 发表时间: 2014-02-04
• 期刊: Cell metabolism
• 影响因子: 29
• 作者: Lee P;Linderman JD;Smith S;Brychta RJ;Wang J;Idelson C;Perron RM;Werner CD;Phan GQ;Kammula US;Kebebew E;Pacak K;Chen KY;Celi FS
• 通讯作者: Celi FS

Furosemide reduces BK-αβ4-mediated K+ secretion in mice on an alkaline high-K+ diet.

呋塞米可减少碱性高 K 饮食小鼠中 BK-αβ4 介导的 K 分泌。

• DOI: 10.1152/ajprenal.00223.2018
• 发表时间: 2019
• 期刊: American journal of physiology. Renal physiology
• 作者: Wang,Bangchen;Wang-France,Jun;Li,Huaqing;Sansom,StevenC
• 通讯作者: Sansom,StevenC

Comparison of Summer and Winter Objectively Measured Physical Activity and Sedentary Behavior in Older Adults: Age, Gene/Environment Susceptibility Reykjavik Study.

• DOI: 10.3390/ijerph14101268
• 发表时间: 2017-10-21
• 期刊: International journal of environmental research and public health
• 作者: Arnardottir NY;Oskarsdottir ND;Brychta RJ;Koster A;van Domelen DR;Caserotti P;Eiriksdottir G;Sverrisdottir JE;Johannsson E;Launer LJ;Gudnason V;Harris TB;Chen KY;Sveinsson T
• 通讯作者: Sveinsson T

Changes in sleep and activity from age 15 to 17 in students with traditional and college-style school schedules.

• DOI: 10.1016/j.sleh.2020.04.009
• 发表时间: 2020-12
• 期刊: Sleep health
• 影响因子: 4.1
• 作者: Stefansdottir R;Rognvaldsdottir V;Gestsdottir S;Gudmundsdottir SL;Chen KY;Brychta RJ;Johannsson E
• 通讯作者: Johannsson E