Normal kidney function requires the close coordination of glomerular filtration and tubular reabsorption in order to prevent major swings in volume status. This coordination is largely mediated by the processes of glomerular tubular balance (GTB) which is the flow dependence of tubular reabsorption, and tubuloglomerular feedback (TGF), which is the negative feedback regulation of nephron filtration rate (SNGFR) by late proximal tubular flow rate (vLP) mediated by the macula-densa-juxtaglomerular apparatus. GTB and TGF combine to constitute a """"""""TGF system"""""""" which defines a two way interdependence of SNGFR and VLP. However, these relations are not fixed and must be allowed to change in order to maintain physiologic flexibility. Changes in the relation of SNGFR and VLP, or TGF adaptation occur over time in response to imposed, sustained elevations in SNGFR and reductions in proxima absorption, as we have demonstrated during the administration of benzolamide, an inhibitor of proximal tubular reabsorption. Online videometric flow velocitometric techniques permit repetitive assessments of TGF compensation and quantitative assessment of the mode of TGF adaptation while monitoring macula densa afferent TGF signals via distal tubule ionic conductivity electrodes and glomerular hemodynamic evaluations of the effector mechanisms of TGF. The elements critical to TGF adaptation are a) changes in loop of Henle - thick ascending limb (TAL) reabsorptive capacity, b) macula densa signal transmission and c) adaptations of the glomerular hemodynamic effector mechanism.
Specific Aim #1 - TGF adapts to sustained reductions in proximal reabsorption due to 1) adaptive increases in Loop of Henle/TAL reabsorption and 2) modifications in nitric oxide synthase (NOS), specifically neuronal NOS (bNOS).
Specific Aim #2 - TGF may function to limit energy consumption linked to loop of Henle reabsorption, and local pO2 and monooxygenase enzyme systems will be assessed with pO2 micro- electrodes, variations in 02 delivery and enzyme inhibitors. The contributions of tubular segments distal to the macula densa to TGF signalling will also be assessed.
Specific Aim #3 - We propose nephrotoxic acute renal failure (uranyl nitrate) represents an example of impaired TGF adaptation, resulting in persistent TGF activation. his may result from inability to increase loop of Henle reabsorption, modify NOS activity or alter TGF signals t he effector mechanisms. Elucidation of the normal mechanisms of TGF adaptation is a prerequisite for the further understanding of renal pathophysiologic conditions which may exhibit impaired TGF adaptation.
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