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）：大电导钙激活钾通道（BK）由一个成孔α亚基（BK-α）和一个辅助β亚基（BK-β 1 -4）组成。BK高血压，由几个实验室用BK-β 1亚基（β 1 KO）敲除的小鼠证实，主要是继发于K的肾处理缺陷的液体潴留的结果，导致高钾性醛固酮增多症。该竞争性更新建议继续研究肾脏BK-α/β 1的调节。我们先前用β 1 KO和β 4 KO确定，BK-α/β 1和BK-α/β 4分别位于远端肾单位的连接小管主细胞（CNT）和闰间细胞（IC）中，具有不同的作用，使K最大化。 当动物被置于高钾饮食时，分泌的每钠重吸收。第一个目的是确定醛固酮和高血浆[K]在增强BK-α/β 1介导的K分泌中的相对作用。第二个目的是探讨BK-α/β 1在Na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，β 1 KO的经前庭K梯度（TTKG）（K分泌驱动力的间接测量）显著降低。这些数据表明，BK-α/β 1用于非ENaC介导的、Na非依赖性K分泌。我们有初步证据表明，Na非依赖性K分泌所需的大的负跨上皮电位是通过pendrin与通过CFTR Cl通道的顶端Cl再循环结合的HCO 3-IC细胞HCO 3分泌的结果。第三个目的是基于我们以前的研究，显示了K和ATP从皮质集合管IC细胞的共依赖转运。本研究目的是研究BK-α/β 4在IC中的作用，即通过高流量诱导的ATP排泄，提高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血浆[K]医源性增加或挤压综合征（导致血浆[K]水平致命性增加）条件下肾BK通道如何处理K具有重要意义。

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

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

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

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