Homeostasis and Tubuloglomerular Feedback

描述（由申请人提供）： 慢性肾脏病（CKD）是大多数终末期肾功能衰竭的前兆，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过程中后期发生的结构变化过程，此时功能性肾脏被瘢痕组织取代。我们认为，这些过程开始是适应机制，植根于生理学，以补偿早期的伤害，然后因为失去控制它们的手段而出错。提出的研究的一般目的不是研究CKD在其后期阶段的形态学或信号传导方面，而是通过在早期CKD的标准模型中应用肾微穿刺方法，即大鼠肾次全切除术（CKD），来研究CKD发作时肾生理学的主要特征。初步证据表明，在面对肾单位数量减少时，在处理盐平衡的过程中，肾脏对肾小管肾小球反馈（TGF）的影响减少，这是一种用于稳定每个肾小球上的物理应力和每个肾单位所需工作的自动调节机制。当TGF的效率被牺牲，以抵消盐稳态的负面影响，长期盐摄入量和肾小球毛细血管壁的动态拉伸-舒张之间出现了正相关关系，这解释了饮食中的盐在CKD中的邪恶作用。基于这一理论，本研究有两个具体目标。第一个目的是建立机制，饮食中的盐脱敏TGF β在大肠杆菌。第二个目的是了解这种TGF对肾脏中流量和压力的动态自动调节是否有影响。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。

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.