The role of the kidney in volume homeostasis critically depends upon coordination of glomerular ultrafiltration (GFR) and tubular reabsorption. This is achieved through the coordinated actions of glomerulotubular balance (GTB) and the tubuloglomerular feedback (TGF) system. Whenever there is a change in concentration of salt in tubular fluid reaching the MD, TGF elicits a reciprocal change in SNGFR. However, the TGF system must adapt over time to sustained changes in MD NaCl concentration and delivery in order to maintain homeostatic efficiency of TGF. Resetting of TGF or 'temporal adaptation'of TGF does occur by changes in nephron blood flow, afferent arteriolar resistance and alteration in SNGFR leading to a new relationship between the MD signal and the efferent vascular response. The acute TGF response occurs within 30 seconds. The immediateTGF response is associated with ATP release from the MD and is mediated by ATP and/or adenosine, possibly via the Al receptor. A second sustained phase of vasoconstriction continues for 30-40 minutes primarily mediated by adenosine. A third phase of temporal adaptation of TGF occurs after 30-40 minutes and requires activity of NOS-1 and COX-2 products, probably as modulators. The mechanisms of temporal adaptation of TGF remain to be elucidated. We will utilize micropuncture techniques, the in vitro microperfused MD/ afferent arteriole-glomerulus's preparation, in vitro proximal tubules and enzyme assays, radioimmunoassays, Western blots and metabolic assessments to answer the following pertinent questions:
Specific aim #1 - We will determine using in vivo and in vitro experiments whether temporal adaptation occurs a) at the level of modification of the MD NaCl signal, b)suppression of transmission of the TGF signal, probably via the extraglomerular mesangial cells to the afferent arteriole and glomerulus or c) via alterations in the responsiveness of efferent vascular resistance.
Specific aim #2 - We propose that tubular reabsorption adapts and increases secondarily in response to the major changes in filtered load after TGF adaptation and these changes depend upon hormonal influences which mediate and modulate TGF activation and temporal adaptation, e.g., adenosine, ATP, angiotensin II (All) and NO from NOS-1.
Specific aim #3 - We will examine 3 conditions of TGF resetting or temporal adaptation which are 1) variations in dietary NaCl and chronic volume expansion (DOCA and high NaCl), 2) acute volume expansion and 3) following contralateral nephrectomy. Do these conditions permit and exhibit further temporal adaptation of TGF? What are the physiologic consequences of preventing temporal adaptation of TGF in the conditions described? Temporal adaptation of TGF is required to maintain homeostatic efficiency of TGF with transitions in physiologic conditions. TGF adaptation is a requirement for a variety of conditions in life;normal growth, changes in dietary NaCl, loss of nephron mass, alterations in proximal tubular reabsorption, acute hypertension, etc. Defining the mechanism of temporal adaptation of TGF is required for complete understanding of long term kidney contribution to volume homeostasis. These studies will also define the role of purinergic (ATP) and adenosine mediated TGF during all 3 phases of TGF.
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