Homeostasis and Tubuloglomerular Feedback

描述(由申请人提供)： 项目摘要/摘要慢性肾脏病(CKD)是大多数终末期肾功能衰竭的先兆，也是心血管疾病的潜在危险因素。最近对CKD的兴趣主要集中在CKD过程中后期发生的结构变化过程，即功能肾被疤痕组织取代。我们认为，这些过程最初是一种适应机制，植根于生理，以补偿早期的伤害，然后因为失去了控制它们的手段而出错。本研究的主要目的不是研究CKD后期的形态或信号方面，而是通过在早期CKD的标准模型即大鼠肾次全切除术(STN)中应用肾脏微穿刺法来研究CKD发病时肾脏的基本生理特征。初步证据表明，在肾单位数量减少的情况下，在维持盐平衡的过程中，STN肾脏减少了对肾小管球球反馈的杠杆作用，这是一种稳定每个肾小球上的物理压力和每个肾单位所需工作的自动调节机制。当牺牲转化生长因子的效率来抵消STN对盐稳态的负面影响时，长期的盐摄入量与肾小球毛细血管壁的动态拉伸-松弛呈正相关，这解释了饮食盐在CKD中的恶毒作用。基于这一理论，本文提出了两个具体的研究目标。第一个目的是建立饮食盐在STN中减敏转化生长因子的机制。第二个目的是了解这种转化生长因子是否会对肾脏内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病患护理任务的相关性：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脏疾病的先决条件。慢性肾脏疾病本身就具有特殊的重要性，因为它显著增加了心血管疾病的可能性。这项研究的总体目的是了解当患病的肾脏被迫在稳定自身功能和回应身体其他需求之间做出选择时会发生什么。这项拟议的研究具有临床意义，因为它可能有助于理解如何优化影响肾功能的信号，以造福于肾脏和患者。

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.