Homeostasis and Tubuloglomerular Feedback

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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.