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。所提出的研究的一般目的是通过在早期CKD的标准模型中应用肾微穿刺方法，即大鼠肾大部切除术（CKD），来研究CKD过程早期的肾生理学的主要特征。我们已经发现，给大鼠喂食高盐饮食在产后第一周导致逆转 肾小管肾小球反馈（TGF）反应从负到正的增益。虽然这将加速盐平衡的恢复，但也意味着肾脏愿意放弃TGF通常赋予的功能和血液动力学稳定性。这种向异常TGF的转变建立了膳食盐摄入量与肾小球毛细血管壁动态拉伸-松弛之间的正相关关系，这可能解释了膳食盐在CKD中的邪恶作用。即将进行的研究将确定这种生理学是否在适应肾单位损失的早期阶段仍然相关，它是否是一个持久的过程，在高NaCl被撤回后仍然存在，它是否依赖于Na，Cl或两者，以及它如何与肾脏代谢相互作用。

DESCRIPTION (provided by applicant): 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 to investigate cardinal features of kidney physiology early in the course of CKD by applying renal micropuncture methods in a standard model for early CKD, namely subtotal nephrectomy (STN) in the rat. We have discovered that feeding high NaCl diet to a rat during the first week after STN leads to a reversal of the tubuloglomerular feedback (TGF) response from negative to positive gain. While this will speed up the return to salt balance, it also signifies that the kidney is willing to forego the functional and hemodynamic stability normally conferred by TGF. This shift to anomalous TGF establishes a positive relationship between dietary salt intake and dynamic stretch-relaxation of the glomerular capillary wall, which may explain the nefarious effect of dietary salt in CKD. The upcoming research will determine whether this physiology remains relevant beyond the early stages of adaptation to nephron loss, whether it is a durable process that persists after high NaCl is withdrawn, whether it depends on Na, Cl, or both, and how it interacts with kidney metabolism.