Homeostasis and Tubuloglomerular Feedback

稳态和肾小球反馈

• 批准号: 7796348
• 负责人: SCOTT Culver THOMSON
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7796348
• 关键词: Affect; Body Fluids; Cardiovascular Diseases; Chronic Kidney Failure; Cicatrix; Data; Diet; End stage renal failure; Engineering; Equilibrium; Feedback; Funding; Glomerular Capillary; Goals; Homeostasis; Individual; Injury; Juxtaglomerular Apparatus; Kidney; Learning; Logic; Methods; Micropuncture; Mission; Modeling; N-Methyl-D-Aspartate Receptors; Nephrectomy; Nephrons; Nitric Oxide; Patient Care; Patients; Physiology; Plant Roots; Process; Rattus; Regulation; Relaxation; Renal function; Research; Research Design; Risk Factors; Role; Signal Transduction; Sodium Chloride; Staging; Stress; Stretching; System; Testing; Tissues; Tubular formation; Ursidae Family; Veterans; Work; abstracting; base; clinically relevant; glomerular filtration; glomerular function; in vivo; interest; novel; pressure; public health relevance; salt balance; salt intake; theories

DESCRIPTION (provided by applicant): Project Summary/Abstract Chronic kidney disease (CKD) is the precursor to most end-stage renal failure and is a potent risk factor for cardiovascular disease. Recent interest in CKD has focused on processes of structural change that occur later in the course of CKD when functioning kidney is replaced by scar tissue. We ascribe to the view that these processes begin as adaptive mechanisms, rooted in physiology, to compensate for an earlier injury, then go awry because the means to control them is lost. It is the general purpose of the proposed research, not to study the morphological or signaling aspects of CKD during these its later stages, but to investigate cardinal features of kidney physiology at the onset of CKD by applying renal micropuncture methods in a standard model for early CKD, namely subtotal nephrectomy (STN) in the rat. Preliminary evidence suggests that, in the course of attending to salt balance in the face of reduced nephron number, the STN kidney affords reduced leverage to tubuloglomerular feedback (TGF), which is an autoregulatory mechanism for stabilizing the physical stress on each glomerulus and the work required of each nephron. When the efficiency of TGF is sacrificed to offset the negative impact of STN on salt homeostasis, there emerges a positive relationship between the long-term salt intake and dynamic stretch-relaxation of the glomerular capillary wall, which explains the nefarious effect of dietary salt in CKD. Based on this theory, the proposed research has 2 specific aims. The first aim is to establish the mechanism whereby dietary salt desensitizes TGF in STN. The second aim is to learn if there are consequences of this TGF for dynamic autoregulation of flow and pressure in the kidney. These aims will be achieved by adapting principles from engineering control theory to micropuncture data in the rat. PUBLIC HEALTH RELEVANCE: Project Narrative Relevance of the Proposed Work to the VA Patient Care Mission: We propose to study kidney physiology because this is prerequisite to understanding chronic kidney disease, which is common among veterans. Chronic kidney disease bears special importance in its own right and because it markedly increases the likelihood of cardiovascular disease. The general purpose of this research is to understand what happens when the diseased kidney is forced to choose between stabilizing its own function and responding to other needs of the body. The proposed research bears clinical relevance for its potential contribution to understanding how to optimize signals that affect kidney function for the benefit of both the kidney and the patient.

描述（由申请人提供）： 项目摘要/摘要 慢性肾脏病 (CKD) 是大多数终末期肾衰竭的先兆，也是心血管疾病的潜在危险因素。最近对 CKD 的兴趣集中在 CKD 病程后期发生的结构变化过程，即功能性肾脏被疤痕组织取代。我们认为这些过程最初是植根于生理学的适应性机制，旨在补偿早期的损伤，然后因为控制它们的手段丧失而出错。本研究的总体目的不是研究 CKD 后期的形态或信号传导方面，而是通过在标准模型中应用肾微穿刺方法来研究 CKD 发病时肾脏生理学的主要特征。 CKD，即大鼠肾次全切除术（STN）。初步证据表明，在面对肾单位数量减少的情况下注意盐平衡的过程中，STN 肾脏对肾小球反馈 (TGF) 的影响力降低，TGF 是一种自动调节机制，用于稳定每个肾小球的身体压力和工作每个肾单位都需要。当牺牲 TGF 的效率来抵消 STN 对盐稳态的负面影响时，长期盐摄入量与肾小球毛细血管壁的动态拉伸松弛之间出现正相关关系，这解释了膳食盐对人体内盐的有害影响。慢性肾病。基于这一理论，所提出的研究有两个具体目标。第一个目标是建立膳食盐使 STN 中 TGF 脱敏的机制。第二个目的是了解这种 TGF 是否会对肾脏中流量和压力的动态自动调节产生影响。这些目标将通过将工程控制理论的原理应用于大鼠的微穿刺数据来实现。 公共卫生相关性： 项目叙述拟议工作与退伍军人管理局患者护理使命的相关性：我们建议研究肾脏生理学，因为这是了解退伍军人中常见的慢性肾病的先决条件。慢性肾脏病本身就具有特别重要的意义，因为它显着增加了患心血管疾病的可能性。这项研究的总体目的是了解当患病肾脏被迫在稳定自身功能和响应身体其他需求之间做出选择时会发生什么。拟议的研究具有临床相关性，因为它可能有助于了解如何优化影响肾功能的信号，从而造福肾脏和患者。