Aquaporin-2 (AQP2) Regulation by AMP-activated kinase(AMPK) in the Kidney Collec

肾集合中 AMP 激活激酶 (AMPK) 调节水通道蛋白 2 (AQP2)

基本信息

项目摘要

DESCRIPTION (provided by applicant): Aquaporin-2 (AQP2) expressed in kidney collecting duct epithelial principal cells is essential for the maintenance of total body volume homeostasis. The hormone arginine vasopressin (AVP; or antidiuretic hormone) is secreted from the hypothalamus/pituitary as a normal response to increased serum osmolality or decreased blood pressure. In principal cells, AVP acts via the vasopressin receptor type II (V2R), leading to a cascade involving cAMP/PKA, AQP2 phosphorylation, apical membrane insertion of AQP2-containing vesicles and water reabsorption from the urine into the interstitium. AQP2 trafficking and subcellular localization are mediated by the phosphorylation status of several Ser residues in the AQP2 C-terminus as well as by ubiquitination status. Indeed, research on AQP2 regulation has shed light on the pathogenesis of diseases such as nephrogenic diabetes insipidus (NDI), SIADH and heart failure. Our preliminary data show that the metabolic sensor AMP-activated kinase (AMPK), which is upregulated by metabolic stress (e.g., during ischemia), prevents acute PKA-mediated AQP2 apical accumulation ex vivo in kidney slices. In addition, dominant-negative AMPK accelerates AQP2-mediated oocyte swelling upon hypotonic shock, suggesting that inhibition of AMPK activity stimulates AQP2 function. We hypothesize that AMPK induces intracellular accumulation of AQP2, either via direct phosphorylation or by modulating PKA-mediated AQP2 phosphorylation, and promotes AQP2 ubiquitination and degradation during periods of metabolic stress. Our aims are to examine the mechanisms by which AMPK-dependent phosphorylation regulates AQP2 trafficking and function and to examine the role of AMPK in enhancing the ubiquitination, cytoplasmic redistribution, and degradation of AQP2. We will determine which AQP2 residues are phosphorylated by AMPK by mass spectrometry and the role of those residues on the subcellular localization and activity of this water channel in oocytes and mpkCCDc14 cells. We will also determine whether AMPK increases AQP2 ubiquitination and degradation in kidney slices and in mpkCCDc14 cells. Finally, we will determine whether AMPK inhibition prevents AQP2 redistribution and/or degradation in kidney slices and mpkCCDc14 cells following chemical ischemia. This proposal addresses a novel potential mechanism by which metabolic stress, as occurs during ischemia, regulates AQP2. Our research will likely contribute to a better understanding of how body water homeostasis may be coupled to metabolism and pathology of vital organs such as heart and kidney. PUBLIC HEALTH RELEVANCE: Aquaporin-2 (AQP2), a water channel expressed in kidney epithelium, is essential for the maintenance of total body volume homeostasis. Research on AQP2 has shed light on the pathogenesis of nephrogenic diabetes insipidus, the syndrome of inappropriate antidiuretic hormone release, and heart failure. We hypothesize that AMPK, which is activated by ischemia, regulates AQP2 abundance and function during acute kidney ischemia. Our research should contribute to a better understanding of how body water homeostasis may be coupled to metabolism and kidney pathology. In addition, it may provide insight into the treatment of important body water balance disorders like nephrogenic diabetes insipidus.
描述(申请人提供):肾集合管上皮主细胞中表达的水通道蛋白-2(AQP2)对于维持总体体积稳态至关重要。精氨酸加压素(AVP;或抗利尿激素)是下丘脑/垂体分泌的激素,是对血清渗透压升高或血压降低的正常反应。在主细胞中,AVP 通过 II 型加压素受体 (V2R) 发挥作用,导致涉及 cAMP/PKA、AQP2 磷酸化、含有 AQP2 的囊泡顶膜插入以及水从尿液重吸收到间质的级联反应。 AQP2 运输和亚细胞定位由 AQP2 C 末端几个 Ser 残基的磷酸化状态以及泛素化状态介导。事实上,对 AQP2 调节的研究揭示了肾性尿崩症 (NDI)、SIADH 和心力衰竭等疾病的发病机制。我们的初步数据表明,代谢传感器 AMP 激活激酶 (AMPK) 通过代谢应激(例如,缺血期间)上调,可防止肾切片中急性 PKA 介导的 AQP2 顶端积累。此外,显性失活的 AMPK 会加速低渗休克时 AQP2 介导的卵母细胞肿胀,表明抑制 AMPK 活性会刺激 AQP2 功能。我们假设 AMPK 通过直接磷酸化或通过调节 PKA 介导的 AQP2 磷酸化来诱导 AQP2 的细胞内积累,并在代谢应激期间促进 AQP2 泛素化和降解。我们的目的是研究 AMPK 依赖性磷酸化调节 AQP2 运输和功能的机制,并研究 AMPK 在增强 AQP2 泛素化、细胞质重新分布和降解中的作用。我们将通过质谱法确定哪些 AQP2 残基被 AMPK 磷酸化,以及这些残基对卵母细胞和 mpkCCDc14 细胞中水通道的亚细胞定位和活性的作用。我们还将确定 AMPK 是否会增加肾切片和 mpkCCDc14 细胞中 AQP2 的泛素化和降解。最后,我们将确定 AMPK 抑制是否会阻止化学缺血后肾切片和 mpkCCDc14 细胞中 AQP2 的重新分布和/或降解。该提案提出了一种新的潜在机制,缺血期间发生的代谢应激可通过该机制调节 AQP2。我们的研究可能有助于更好地了解体内水分稳态如何与心脏和肾脏等重要器官的新陈代谢和病理学相联系。 公共卫生相关性:水通道蛋白-2 (AQP2) 是一种在肾上皮细胞中表达的水通道,对于维持总体体积稳态至关重要。 AQP2 的研究揭示了肾性尿崩症、抗利尿激素释放不当综合征和心力衰竭的发病机制。我们假设由缺血激活的 AMPK 在急性肾缺血期间调节 AQP2 丰度和功能。我们的研究应有助于更好地了解体内水分稳态如何与新陈代谢和肾脏病理学相联系。此外,它还可以为治疗肾性尿崩症等重要的身体水平衡紊乱提供见解。

项目成果

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Mohammad Al-bataineh其他文献

Mohammad Al-bataineh的其他文献

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{{ truncateString('Mohammad Al-bataineh', 18)}}的其他基金

Role of the MUC1/HIF-1a Complex in the kidney proximal tubule during ischemia-reperfusion injury.
MUC1/HIF-1a 复合物在缺血再灌注损伤期间肾近曲小管中的作用。
  • 批准号:
    10349156
  • 财政年份:
    2021
  • 资助金额:
    $ 5.19万
  • 项目类别:
Role of the MUC1/HIF-1a Complex in the kidney proximal tubule during ischemia-reperfusion injury.
MUC1/HIF-1a 复合物在缺血再灌注损伤期间肾近曲小管中的作用。
  • 批准号:
    10541885
  • 财政年份:
    2021
  • 资助金额:
    $ 5.19万
  • 项目类别:
Role of Muc1 in the b-catenin Response to Acute Kidney Injury
Muc1 在 b-catenin 对急性肾损伤反应中的作用
  • 批准号:
    10440020
  • 财政年份:
    2016
  • 资助金额:
    $ 5.19万
  • 项目类别:
Role of Muc1 in the b-catenin Response to Acute Kidney Injury
Muc1 在 b-catenin 对急性肾损伤反应中的作用
  • 批准号:
    10323751
  • 财政年份:
    2016
  • 资助金额:
    $ 5.19万
  • 项目类别:
Aquaporin-2 (AQP2) Regulation by AMP-activated kinase(AMPK) in the Kidney Collec
肾集合中 AMP 激活激酶 (AMPK) 调节水通道蛋白 2 (AQP2)
  • 批准号:
    8630873
  • 财政年份:
    2013
  • 资助金额:
    $ 5.19万
  • 项目类别:

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线粒体能量的多模式控制塑造生物衰老
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