Renal Regulation of the Magnesium Channel TRPM6 by Uromodulin

尿调节蛋白对镁通道 TRPM6 的肾脏调节

基本信息

项目摘要

PROJECT SUMMARY/ABSTRACT Up to 15% of the population has hypomagnesemia which is associated with a higher risk of developing common disorders like diabetes mellitus type 2 and hypertension. Urinary Mg2+ losses contribute to hypomagnesemia, but knowledge about renal Mg2+ homeostasis is very limited. This proposal seeks to improve our understanding of renal Mg2+ homeostasis. The major organ for regulated Mg2+ reabsorption is the kidney. The final urinary Mg2+ concentration is determined by the epithelial Mg2+ channel TRPM6 in the distal convoluted tubule (DCT). Uromodulin (Umod) is a possible new modifier of renal Mg2+ handling as Umod gene expression is increased in hypomagnesemic mice. Our preliminary data confirm urinary Mg2+ wasting in Umod knock-out (Umod-/-) mice. In addition, we found increased TRPM6 whole-cell current density and TRPM6 cell surface abundance with UMOD expression. Our overall objective of this application is to study the effect of the urinary protein UMOD regarding the regulation of the Mg2+ channel TRPM6. Our preliminary results raise a novel hypothesis that UMOD, secreted from TAL, upregulates TRPM6 activity in the DCT from the luminal side by impairing TRPM6 endocytosis, thereby increasing channel cell surface abundance and so enhancing tubular Mg2+ reabsorption. We hypothesize that in low Mg2+ conditions, tubular UMOD secretion increases which then enhances renal Mg2+ reabsorption via TRPM6 to mitigate Mg2+ losses. In aim 1, we will test this hypothesis in vitro by analyzing the mechanism by which extracellular UMOD regulates TRPM6 activity. Using whole-cell patch-clamp recording and protein biochemistry in cultured cell expression systems, we will test if UMOD increases TRPM6 cell surface abundance by impairing TRPM6 endocytosis and examine which UMOD domains are required for TRPM6 regulation. In aim 2, we will test the role of UMOD regarding renal Mg2+ handling in vivo. We will examine by immunofluorescent imaging if urinary Mg2+ wasting in Umod-/- mice is due to decreased apical TRPM6 expression. To study if UMOD is part of a renal feedback mechanism responding to systemic Mg2+ changes, we will analyze the response of wild-type and Umod-/- mice challenged with normal, low and high Mg2+ diets. Given our experience in ion channel physiology, mouse physiology, TRP channels and UMOD, we are very well equipped to perform this study. The contribution of this work will be significant as renal Mg2+ regulation by a urinary protein represents a novel concept. We expect a positive translational impact of this project, as the proposed feedback mechanism targeting systemic Mg2+ homeostasis may provide a novel explanation for a predisposition for urinary Mg2+ wasting. As UMOD polymorphisms affect urinary UMOD secretion, we will test in a future R01 application in a human cohort if UMOD polymorphisms contribute to urinary Mg2+ wasting by decreased UMOD secretion and if these UMOD polymorphisms are associated with common disorders. We hypothesize that specific UMOD polymorphisms reduce an individual’s adaptability to adjust to low Mg2+ conditions which could provide a link between hypomagnesemia and common disorders.
项目总结/摘要 高达15%的人口患有低镁血症,这与发展的风险较高有关。 2型糖尿病和高血压等常见疾病。尿Mg 2+丢失导致 低镁血症,但有关肾脏Mg 2+稳态的知识非常有限。这项建议旨在 提高我们对肾脏Mg 2+稳态的了解。调节Mg 2+重吸收的主要器官是 肾最终的尿Mg 2+浓度由远端的上皮Mg 2+通道TRPM 6决定。 曲小管(DCT)。尿调素(Umod)可能是一种新的肾脏镁离子转运调节基因 在低镁血症小鼠中表达增加。我们的初步数据证实尿镁2+浪费在Umod 敲除(Umod-/-)小鼠。此外,我们发现TRPM 6全细胞电流密度和TRPM 6细胞 表面丰度与UMOD表达。本申请的总体目标是研究 尿蛋白UMOD关于Mg 2+通道TRPM 6的调节。我们的初步结果提出了一个 TAL分泌的UMOD从管腔侧上调DCT中TRPM 6活性的新假设 通过削弱TRPM 6内吞作用,从而增加通道细胞表面丰度, 肾小管镁重吸收。我们假设在低镁条件下,肾小管UMOD分泌增加, 然后通过TRPM 6增强肾Mg 2+重吸收以减轻Mg 2+损失。在目标1中,我们将测试这一点 通过分析细胞外UMOD调节TRPM 6活性的机制,在体外验证了这一假说。使用 全细胞膜片钳记录和蛋白质生物化学在培养的细胞表达系统,我们将测试, UMOD通过损害TRPM 6内吞作用增加TRPM 6细胞表面丰度,并检查UMOD 域是TRPM 6法规所必需的。在目标2中,我们将测试UMOD对肾脏Mg 2+的作用 体内处理。我们将通过免疫荧光成像来检查Umod-/-小鼠中尿Mg 2+消耗是否是由于 降低顶端TRPM 6的表达。研究UMOD是否是肾反馈机制的一部分, 对于全身Mg 2+变化,我们将分析野生型和Umod-/-小鼠用正常, 低镁和高镁日粮。鉴于我们在离子通道生理学、小鼠生理学、TRP通道 和UMOD,我们有很好的设备来进行这项研究。这项工作的贡献将是重大的,因为 通过尿蛋白进行的肾Mg 2+调节代表了一个新的概念。我们期待积极的转化影响 由于所提出的针对全身Mg 2+稳态的反馈机制可能提供了一个 尿镁消耗倾向的新解释。由于UMOD多态性影响尿UMOD 因此,我们将在未来的R 01应用中在人类队列中测试UMOD多态性是否有助于 UMOD分泌减少导致的尿Mg 2+消耗,如果这些UMOD多态性与 常见疾病我们假设特定的UMOD多态性降低了个体的适应性, 调整到低镁2+条件,这可能提供低镁血症和常见疾病之间的联系。

项目成果

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Matthias Tilmann Florian Wolf其他文献

Matthias Tilmann Florian Wolf的其他文献

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{{ truncateString('Matthias Tilmann Florian Wolf', 18)}}的其他基金

Assay Development and Optimization for High Throughput Screen to Detect Compounds Increasing Secretion of C150S Mutant Uromodulin
用于检测增加 C150S 突变体尿调节蛋白分泌的化合物的高通量筛选的测定方法开发和优化
  • 批准号:
    10311119
  • 财政年份:
    2020
  • 资助金额:
    $ 8.1万
  • 项目类别:
Assay Development and Optimization for High Throughput Screen to Detect Compounds Increasing Secretion of C150S Mutant Uromodulin
用于检测增加 C150S 突变体尿调节蛋白分泌的化合物的高通量筛选的测定方法开发和优化
  • 批准号:
    10534214
  • 财政年份:
    2020
  • 资助金额:
    $ 8.1万
  • 项目类别:
The Role of Uromodulin in the Regulation of the Renal Calcium Channel TRPV5
尿调节蛋白在肾钙通道 TRPV5 调节中的作用
  • 批准号:
    8683168
  • 财政年份:
    2012
  • 资助金额:
    $ 8.1万
  • 项目类别:
The Role of Uromodulin in the Regulation of the Renal Calcium Channel TRPV5
尿调节蛋白在肾钙通道 TRPV5 调节中的作用
  • 批准号:
    8507230
  • 财政年份:
    2012
  • 资助金额:
    $ 8.1万
  • 项目类别:
The Role of Uromodulin in the Regulation of the Renal Calcium Channel TRPV5
尿调节蛋白在肾钙通道 TRPV5 调节中的作用
  • 批准号:
    8353943
  • 财政年份:
    2012
  • 资助金额:
    $ 8.1万
  • 项目类别:
The Role of Uromodulin in the Regulation of the Renal Calcium Channel TRPV5
尿调节蛋白在肾钙通道 TRPV5 调节中的作用
  • 批准号:
    8893974
  • 财政年份:
    2012
  • 资助金额:
    $ 8.1万
  • 项目类别:

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