Regulation of Renal WNK Signaling in Intercalated Cells

闰细胞中肾脏 WNK 信号传导的调节

基本信息

项目摘要

The kidneys play a primary role in the maintenance of potassium homeostasis. The aldosterone sensitive distal nephron (ASDN) regulates potassium balance by matching the rate of urinary K+ excretion with changes in extracellular [K+]. Intercalated cells (ICs) play an important role in this process. Within these cells, apical large conductance BK channels open in response to shear stress to facilitate flow-induced K+ secretion (FIKS), a process activated by hyperkalemia. Though ICs mediate the transcellular movement of K+ from the peritubular interstitium into the tubule lumen, they are unique in that their basolateral K+ entry step is not carried out by the Na+/K+-ATPase. Instead, current evidence suggests that this process requires a bumetanide-sensitive Na+-K+-2Cl- cotransporter, NKCC1 (SLC12A2). NKCC1 is activated via direct phosphorylation, a process mediated by the WNK-SPAK/OSR1 pathway. Consistent with a role for this pathway in FIKS, we find that the kinase active forms of WNK1 and SPAK are stimulated in ICs during hyperkalemia, likely to activate basolateral NKCC1 and apical BK channels. This, however, contradicts the current paradigm, which contends that WNK kinases should be switched off when potassium levels are high in the blood. The overall goal of this application is to determine the importance of NKCC1 and the WNK-SPAK/OSR1 pathway in FIKS, and to test a novel mechanism that explains how these proteins are specifically activated in ICs of the ASDN during hyperkalemia. To accomplish this objective, we will use a variety experimental approaches, including whole animal studies, transport measurements in isolated perfused tubules, fluorescent cell sorting and isolation of ICs derived from whole kidney, and in vitro studies in cell culture models. The information gained from these studies will advance our knowledge of the molecular mechanisms underlying the ASDN’s response to potassium stress.
肾脏在维持钾稳态中起主要作用。醛固酮敏感性远端 肾单位(ASDN)通过使尿K+排泄速率与 细胞外[K+]。嵌入细胞(IC)在这一过程中起着重要的作用。在这些细胞中,顶端大 电导BK通道响应于剪切应力而打开,以促进流动诱导的K+分泌(FIKS), 由高钾血症激活的过程。尽管IC介导K+从管周的跨细胞运动 它们的独特之处在于,它们的基底外侧K+进入步骤不是通过 Na+/K+-ATP酶。相反,目前的证据表明,这个过程需要对布美他尼敏感的 Na+-K+-2Cl-协同转运蛋白,NKCC 1(SLC 12 A2)。NKCC 1通过直接磷酸化激活, 通过WNK-SPAK/OSR 1途径介导。与此通路在FIKS中的作用一致,我们发现, 在高钾血症期间,在IC中刺激WNK 1和SPAK的激酶活性形式,可能激活 基底外侧NKCC 1和顶端BK通道。然而,这与当前的范式相矛盾, 当血液中钾水平高时,WNK激酶应该被关闭。这个项目的总体目标是 应用是确定NKCC 1和WNK-SPAK/OSR 1通路在FIKS中的重要性,并测试 一种新的机制,解释了这些蛋白质是如何在ASDN的IC中特异性激活的, 高钾血症为了实现这一目标,我们将使用各种实验方法,包括整体 动物研究,在离体灌流小管中的转运测量,荧光细胞分选和 来自全肾的IC,以及细胞培养模型中的体外研究。从这些获得的信息 研究将推进我们对ASDN应答的分子机制的认识, 钾胁迫

项目成果

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AROHAN R SUBRAMANYA其他文献

AROHAN R SUBRAMANYA的其他文献

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{{ truncateString('AROHAN R SUBRAMANYA', 18)}}的其他基金

Model Systems Core
模型系统核心
  • 批准号:
    10747626
  • 财政年份:
    2023
  • 资助金额:
    $ 38.37万
  • 项目类别:
Regulation of Renal WNK Signaling in Intercalated Cells
闰细胞中肾脏 WNK 信号传导的调节
  • 批准号:
    10440321
  • 财政年份:
    2019
  • 资助金额:
    $ 38.37万
  • 项目类别:
Regulation of Renal WNK Signaling in Intercalated Cells
闰细胞中肾脏 WNK 信号传导的调节
  • 批准号:
    10214600
  • 财政年份:
    2019
  • 资助金额:
    $ 38.37万
  • 项目类别:
Regulation of Renal WNK Signaling in Intercalated Cells
闰细胞中肾脏 WNK 信号传导的调节
  • 批准号:
    10662286
  • 财政年份:
    2019
  • 资助金额:
    $ 38.37万
  • 项目类别:
Epithelial Transport Group Sessions at Experimental Biology 2016
2016 年实验生物学上皮运输小组会议
  • 批准号:
    9126078
  • 财政年份:
    2016
  • 资助金额:
    $ 38.37万
  • 项目类别:
Characterization and Control of the Renal WNK1 Signaling Pathway
肾脏 WNK1 信号通路的表征和控制
  • 批准号:
    9040930
  • 财政年份:
    2014
  • 资助金额:
    $ 38.37万
  • 项目类别:
Characterization and Control of the Renal WNK1 Signaling Pathway
肾脏 WNK1 信号通路的表征和控制
  • 批准号:
    9249040
  • 财政年份:
    2014
  • 资助金额:
    $ 38.37万
  • 项目类别:
Characterization and Control of the Renal WNK1 Signaling Pathway
肾脏 WNK1 信号通路的表征和控制
  • 批准号:
    8694696
  • 财政年份:
    2014
  • 资助金额:
    $ 38.37万
  • 项目类别:
WNK1 regulation of renal NaCl cotransport
WNK1 对肾脏 NaCl 共转运的调节
  • 批准号:
    7125600
  • 财政年份:
    2005
  • 资助金额:
    $ 38.37万
  • 项目类别:
WNK1 regulation of renal NaCl cotransport
WNK1 调节肾脏 NaCl 共转运
  • 批准号:
    6994234
  • 财政年份:
    2005
  • 资助金额:
    $ 38.37万
  • 项目类别:

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醛固酮合酶的持续合成能力和催化机制
  • 批准号:
    10600520
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