Cellular Mechanisms for Tubuloglomerular Feedback

肾小球反馈的细胞机制

• 批准号: 7033818
• 负责人: Phillip Darwin Bell
• 金额: $ 7.06万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7033818
• 关键词: PC12 cells; adenosine; adenosine triphosphate; basolateral membrane; biological signal transduction; calcium flux; cell morphology; confocal scanning microscopy; fluorescence microscopy; hemodynamics; intracellular transport; kidney circulation; laboratory rabbit; membrane channels; mesangium; mitochondrial membrane; purinergic receptor; renal glomerulus; renal tubular transport; renal tubule; sodium chloride; voltage /patch clamp

DESCRIPTION (provided by applicant): Macula densa cells are located within the thick ascending limb; they detect changes in luminal fluid composition and transmit signals to the afferent arteriole, a process called tubuloglomerular feedback. Considerable effort has been directed towards elucidation of transport characteristics of these cells, in identifying the nature of mediator(s) that are released by macula densa cells and the signals that are sent to the underlying mesangial/afferent arteriolar complex. We have found that increases in luminal fluid sodium chloride concentration ([NaCI]L) activate a maxi anion channel leading to the movement of ATP across the basolateral membrane and direct, or with conversion to adenosine, afferent arteriole vasoconstriction and decreased GFR. This renewal is focused on an in depth analysis of this ATP signaling pathway. Studies will use the isolated perfused thick ascending limb-glomerular preparation and 2-photon microscopy, patch clamp, and molecular biology. Aim one is to elucidate the intracellular events that lead to the release of ATP across the basolateral membrane. We will test the hypothesis that macula densa cells exhibit unique properties of cytosolic calcium concentration [Ca2+], regulation and that [Ca2+]j plays a critical role in macula densa signaling. Studies will also define roles for macula densa cell volume and tubular flow in [Ca2+]j regulation and macula densa signaling. Aim two will test the hypothesis that increased macula densa [Ca2+]j results in mitochondrial Ca2+ uptake and enhanced ATP generation. Other work will define the intracellular events that activate the maxi anion channel and finally we will work towards defining the molecular identity of this ATP conductive pathway. Aim three will explore the role of ATP signaling to the mesangial/afferent arteriolar complex. Overall these studies should provide important new information regarding the role of ATP in macula densa signaling, activation of the tubuloglomerular feedback mechanism, and control of glomerular hemodynamics.

描述（由申请人提供）：黄斑densa细胞位于较厚的上升肢体内；他们检测出腔流体组成的变化并将信号传输到传入小动脉，这一过程称为肾小球斜体反馈。已经大力努力阐明这些细胞的运输特征，以识别大黄斑densa细胞释放的介体的性质以及发送到基本的膜/传入小动脉复合物的信号。我们发现，腔液氯化钠浓度（[NACI] L）的增加会激活一个最大阴离子通道，从而导致ATP在基底外侧膜和直接转化，或转化为腺苷，传入小动脉血管收缩和减少GFR。该更新集中在对此ATP信号通路的深入分析上。研究将使用孤立的灌注较厚的升高肢体形式制剂以及2光子显微镜，斑块夹和分子生物学。目的是阐明导致ATP在基底外侧膜中释放的细胞内事件。我们将检验以下假设：黄斑丁萨细胞表现出胞质钙浓度的独特特性[Ca2+]，调节，[Ca2+] J J在黄斑densa信号传导中起关键作用。研究还将定义[Ca2+] J调节和黄斑densa信号传导中黄斑densa细胞体积和管状流量的作用。目标两个将检验以下假设，即增加黄斑densa [Ca2+] j会导致线粒体Ca2+摄取和增强ATP的产生。其他工作将定义激活最大阴离子通道的细胞内事件，最后我们将致力于定义该ATP导电途径的分子身份。 AIM三将探讨ATP信号对膜/传入小动脉复合体的作用。总体而言，这些研究应提供有关ATP在黄斑densa信号传导中的作用，肾小管斜体反馈机制的激活以及肾小球血液动力学的控制的重要新信息。