AUTOREGULATION OF GLOMERULAR FILTRATION RATE

肾小球滤过率的自动调节

• 批准号: 6140322
• 负责人: ROLAND C BLANTZ
• 金额: $ 6.44万
• 依托单位: VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2000-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6140322
• 关键词: acute renal failure; bioenergetics; blood flow measurement; enzyme activity; enzyme inhibitors; enzyme mechanism; glomerular filtration rate; hemodynamics; homeostasis; laboratory rat; micropuncture; nitric oxide synthase; oxygen microelectrode; oxygen tension; oxygenases; renal tubular transport

Normal kidney function requires the close coordination of glomerular filtration and tubular reabsorption in order to prevent major swings in volume status. This coordination is largely mediated by the processes of glomerular tubular balance (GTB) which is the flow dependence of tubular reabsorption, and tubuloglomerular feedback (TGF), which is the negative feedback regulation of nephron filtration rate (SNGFR) by late proximal tubular flow rate (vLP) mediated by the macula-densa-juxtaglomerular apparatus. GTB and TGF combine to constitute a "TGF system" which defines a two way interdependence of SNGFR and VLP. However, these relations are not fixed and must be allowed to change in order to maintain physiologic flexibility. Changes in the relation of SNGFR and VLP, or TGF adaptation occur over time in response to imposed, sustained elevations in SNGFR and reductions in proxima absorption, as we have demonstrated during the administration of benzolamide, an inhibitor of proximal tubular reabsorption. Online videometric flow velocitometric techniques permit repetitive assessments of TGF compensation and quantitative assessment of the mode of TGF adaptation while monitoring macula densa afferent TGF signals via distal tubule ionic conductivity electrodes and glomerular hemodynamic evaluations of the effector mechanisms of TGF. The elements critical to TGF adaptation are a) changes in loop of Henle - thick ascending limb (TAL) reabsorptive capacity, b) macula densa signal transmission and c) adaptations of the glomerular hemodynamic effector mechanism. Specific Aim #1- TGF adapts to sustained reductions in proximal reabsorption due to 1) adaptive increases in Loop of Henle/TAL reabsorption and 2) modifications in nitric oxide synthase (NOS), specifically neuronal NOS (bNOS). Specific Aim #2- TGF may function to limit energy consumption linked to loop of Henle reabsorption, and local pO2 and monooxygenase enzyme systems will be assessed with pO2 micro- electrodes, variations in 02 delivery and enzyme inhibitors. The contributions of tubular segments distal to the macula densa to TGF signalling will also be assessed. Specific Aim #3 - We propose nephrotoxic acute renal failure (uranyl nitrate) represents an example of impaired TGF adaptation, resulting in persistent TGF activation. his may result from inability to increase loop of Henle reabsorption, modify NOS activity or alter TGF signals t he effector mechanisms. Elucidation of the normal mechanisms of TGF adaptation is a prerequisite for the further understanding of renal pathophysiologic conditions which may exhibit impaired TGF adaptation.

正常的肾功能需要密切的肾小球协调 过滤和管状重吸收，以防止重大波动 音量状态。这种协调在很大程度上是由 肾小球肾小管平衡（GTB），这是管状的流动依赖性 重吸收和肾小管斜体反馈（TGF），这是负的 肾脏过滤率（SNGFR）的反馈调节 肾小管流速（VLP）由大黄斑 - 二曲霉介导的 设备。 GTB和TGF组合构成一个“ TGF系统”，该系统 定义了SNGFR和VLP的两种相互依存关系。但是，这些 关系不是固定的，必须允许改变 保持生理灵活性。 SNGFR和SNGFR关系的变化 VLP或TGF适应会随着时间的推移而响应于施加的，持续的 SNGFR的升高和吸收率的降低，因为我们已经 在给药期间证明了苯甲酰胺， 近端管状重吸收。 在线视频测量值速度测量学 技术允许对TGF补偿的重复评估和 监测时TGF适应方式的定量评估 黄斑densa传入TGF信号通过远端小管离子电导率 效应子的电极和肾小球血流动力学评估 TGF的机制。 TGF适应至关重要的元素是a） Henle环路的变化 - 厚的肢体（TAL）重吸收性 容量，b）黄斑densa信号传递和c）适应 肾小球血流动力学效应器机制。特定目标＃1- TGF适应 持续减少由于1）自适应而导致的近端重吸收 增加Henle/TAL重吸收和2）修改的循环增加 一氧化氮合酶（NOS），特别是神经元NOS（BNO）。具体的 目的＃2- TGF可能会起作用，以限制与循环相关的能源消耗 Henle重吸收以及本地PO2和单加氧酶系统将 用PO2微电极评估，02输送的变化和 酶抑制剂。管状片段远端的贡献 也将评估Macula densa至TGF信号传导。特定目标＃3- 我们提出肾毒性急性肾衰竭（硝酸铀酰）代表 TGF适应受损的一个例子，导致持续的TGF 激活。他的可能是由于无法增加亨尔的循环而造成的 重吸收，修改NOS活性或更改tgf信号效应器 机制。阐明TGF适应的正常机制是一个 进一步理解肾脏病理生理学的先决条件 可能表现出TGF适应受损的条件。