Autoregulation of Glomerular Filtration Rate

肾小球滤过率的自动调节

基本信息

批准号：
7570617
负责人：
ROLAND C BLANTZ
金额：
$ 33.96万
依托单位：
VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
1982
资助国家：
美国
起止时间：
1982-02-01 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7570617
关键词：
Acute Adenosine Affect Angiotensin II Animals Biological Assay Blood Pressure Blood Vessels Blood flow Categories Cells Chronic Coin Contralateral DOCA Dependence Distal Elements Environment Enzymes Equilibrium Event Exhibits Extraglomerular Mesangial Cell Feedback Generations Glomerular Filtration Rate Growth Hand Henle&apos s loop Homeostasis Hormonal Hour Hypertension Imaging Techniques In Vitro Individual Juxtaglomerular Apparatus Kidney Knowledge Learning Life Liquid substance Macula densa Measures Mediating Mediator of activation protein Metabolic Methods Micropuncture Modeling Modification Nephrectomy Nephrons Nitric Oxide Operating System PTGS2 gene Phase Physiological Physiological Processes Physiology Pregnancy Preparation Process Radioimmunoassay Rattus Regulation Research Resistance Role Signal Transduction Sodium Chloride Stimulus Structure of glomerular mesangium System Techniques Testing Time Tubular formation Ultrafiltration Variant Vascular resistance Western Blotting Work arteriole base desensitization extracellular falls in vivo insight interest kidney vascular structure macula meetings novel paracrine prevent receptor research study response salt balance transmission process uptake vasoconstriction

项目摘要

DESCRIPTION (provided by applicant): The role of the kidney in volume homeostasis critically depends upon coordination of glomerular ultrafiltration (GFR) and tubular reabsorption. This is achieved through the coordinated actions of glomerulotubular balance (GTB) and the tubuloglomerular feedback (TGF) system. Whenever there is a change in concentration of salt in tubular fluid reaching the MD, TGF elicits a reciprocal change in SNGFR. However, the TGF system must adapt over time to sustained changes in MD NaCl concentration and delivery in order to maintain homeostatic efficiency of TGF. Resetting of TGF or 'temporal adaptation' of TGF does occur by changes in nephron blood flow, afferent arteriolar resistance and alteration in SNGFR leading to a new relationship between the MD signal and the efferent vascular response. The acute TGF response occurs within 30 seconds. The immediateTGF response is associated with ATP release from the MD and is mediated by ATP and/or adenosine, possibly via the Al receptor. A second sustained phase of vasoconstriction continues for 30-40 minutes primarily mediated by adenosine. A third phase of temporal adaptation of TGF occurs after 30-40 minutes and requires activity of NOS-1 and COX-2 products, probably as modulators. The mechanisms of temporal adaptation of TGF remain to be elucidated. We will utilize micropuncture techniques, the in vitro microperfused MD/ afferent arteriole-glomerulus's preparation, in vitro proximal tubules and enzyme assays, radioimmunoassays, Western blots and metabolic assessments to answer the following pertinent questions: Specific aim #1- We will determine using in vivo and in vitro experiments whether temporal adaptation occurs a) at the level of modification of the MD NaCl signal, b)suppression of transmission of the TGF signal, probably via the extraglomerular mesangial cells to the afferent arteriole and glomerulus or c) via alterations in the responsiveness of efferent vascular resistance. Specific aim #2 - We propose that tubular reabsorption adapts and increases secondarily in response to the major changes in filtered load after TGF adaptation and these changes depend upon hormonal influences which mediate and modulate TGF activation and temporal adaptation, e.g., adenosine, ATP, angiotensin II (All) and NO from NOS-1. Specific aim #3 - We will examine 3 conditions of TGF resetting or temporal adaptation which are 1) variations in dietary NaCl and chronic volume expansion (DOCA and high NaCl), 2) acute volume expansion and 3) following contralateral nephrectomy. Do these conditions permit and exhibit further temporal adaptation of TGF? What are the physiologic consequences of preventing temporal adaptation of TGF in the conditions described? Temporal adaptation of TGF is required to maintain homeostatic efficiency of TGF with transitions in physiologic conditions. TGF adaptation is a requirement for a variety of conditions in life; normal growth, changes in dietary NaCl, loss of nephron mass, alterations in proximal tubular reabsorption, acute hypertension, etc. Defining the mechanism of temporal adaptation of TGF is required for complete understanding of long term kidney contribution to volume homeostasis. These studies will also define the role of purinergic (ATP) and adenosine mediated TGF during all 3 phases of TGF.

描述（由申请人提供）：肾脏在体积稳态中的作用严重取决于肾小球超滤（GFR）和管状重吸收的协调。这是通过肾小球平衡（GTB）和肾小管斜体反馈（TGF）系统的协调作用来实现的。每当到达MD的管状液中的盐浓度变化时，TGF就会引起SNGFR的相互变化。但是，TGF系统必须随着时间的流逝而适应MD NaCl浓度和输送的持续变化，以维持TGF的稳态效率。通过变化，肾血流流动，传入小动脉抗性和SNGFR的改变会导致TGF的TGF或TGF的“时间适应性”的重置，从而导致MD信号与传出血管反应之间存在新的关系。急性TGF响应发生在30秒内。即时ETIATETGF响应与ATP从MD释放有关，并由ATP和/或腺苷介导，可能是通过AL受体介导的。血管收缩的第二个持续期继续进行30-40分钟，主要由腺苷介导。 TGF的时间适应的第三阶段发生在30-40分钟后发生，需要NOS-1和COX-2产品的活性，可能是调节剂。 TGF时间适应的机制仍有待阐明。 We will utilize micropuncture techniques, the in vitro microperfused MD/ afferent arteriole-glomerulus's preparation, in vitro proximal tubules and enzyme assays, radioimmunoassays, Western blots and metabolic assessments to answer the following pertinent questions: Specific aim #1- We will determine using in vivo and in vitro experiments whether temporal adaptation occurs a) at MD NaCl信号的修饰水平，b）TGF信号的传播抑制，可能是通过向传入小动脉和肾小球的偏外膜细胞或c）通过改变传递血管抗性的反应性而进行的。具体目的＃2-我们提出，肾小管重吸收适应性并增加了TGF适应后过滤负荷的主要变化，这些变化取决于激素影响，这些影响介导和调节TGF激活和时间适应性，例如腺苷，ATP，ATP，ATP，ATP，血管素II（ALL）和NO。特定目的＃3-我们将检查3种TGF复位或时间适应的条件，即1）饮食中NaCl和慢性体积膨胀的变化（DOCA和高NACL），2）急性体积扩张和3）对侧肾切除术后。这些条件是否允许并进一步表现出TGF的时间适应？在所述条件下，防止TGF时间适应时间的生理后果是什么？需要TGF的时间适应来维持TGF的稳态效率，并在生理条件下进行过渡。 TGF适应是对生活中各种疾病的要求。正常的生长，饮食NaCl的变化，肾单位质量的损失，近端管状重吸收的改变，急性高血压等。定义TGF时间适应的机制，以完全了解长期肾脏对体积体内稳态的贡献。这些研究还将定义嘌呤能（ATP）和腺苷介导的TGF在TGF的所有三个阶段中的作用。