Blood flow to single renal tubules is regulated by an ensemble of non-linear mechanisms that oscillate in normal animals. One of the mechanisms is tubuloglomerular feedback (TGF), which transmits information about tubular flow rate dependent distal tubule NaCI concentration to the renal afferent arteriole. The other is the myogenic mechanism, a pressure dependent mechanism active in the afferent arteriole that generates spontaneous vasomotion. TGF has the larger, slower oscillation, and the two interact and become phase coupled. TGF's oscillation has 3-5 times the amplitude of the myogenic mechanism's, and is 1/5 as frequent. The TGF oscillation becomes irregular in animals with chronic hypertension; the irregularity has characteristics of non-linear determinism, and the change is referred to as a bifurcation. The major goal of this project is to understand the physiological basis for the bifurcation. A computer simulation of the tubule and its blood vessels will be used to determine the cause. The model has 3 components: 1) a spatially extended model of a renal tubule, with 3 partial differential equations to express dependence of tubular flow rate, tubular pressure, and tubular NaCI concentration on tubular length and time; 2) a single non-linear ordinary differential equation to model glomerular filtration rate; and 6 non- linear ordinary differential equations to model each of two arteriolar segments. The arteriolar model expresses the interaction of K and Ca fluxes to generate action potentials and an autonomous limit cycle oscillation of intracellular Ca, and the Ca oscillation drives myosin light chain phosphorylation, which controls the contractile process and is in parallel with elastic elements. TGF input is linked to Ca entry through voltage gated Ca channels. The model provides excellent blood flow regulation, TGF and myogenic oscillations of appropriate magnitude and frequency, and quadratic phase coupling. It also predicts frequency modulation of the myogenic frequency by TGF, a prediction we have now verified in experimental records. Four hypotheses about the cause of the bifurcation will be tested: that it is caused by a 1/f process in arterial pressure that has more power in some hypertensive rats; that it is caused by increased TGF- myogenic coupling; that it is caused by increased internephron coupling in hypertension; and that it is caused by altered patterns of tubular NaCI reabsorption in hypertension. The revised proposal answers questions raised in the first review, and presents new results from simulations of coupled cortical and medullary nephrons.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB003508-02
Application #
7128122
Study Section
Cellular and Molecular Biology of the Kidney Study Section (CMBK)
Program Officer
Peng, Grace
Project Start
2005-09-28
Project End
2008-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
2
Fiscal Year
2006
Total Cost
$242,617
Indirect Cost
Name
Brown University
Department
Physiology
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
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Marsh, Donald J; Toma, Ildiko; Sosnovtseva, Olga V et al. (2009) Electrotonic vascular signal conduction and nephron synchronization. Am J Physiol Renal Physiol 296:F751-61
Sosnovtseva, Olga V; Pavlov, Alexey N; Mosekilde, Erik et al. (2007) Synchronization among mechanisms of renal autoregulation is reduced in hypertensive rats. Am J Physiol Renal Physiol 293:F1545-55
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Ditlevsen, Susanne; Yip, Kay-Pong; Marsh, Donald J et al. (2007) Parameter estimation of feedback gain in a stochastic model of renal hemodynamics: differences between spontaneously hypertensive and Sprague-Dawley rats. Am J Physiol Renal Physiol 292:F607-16
Raghavan, Ramakrishna; Chen, Xinnian; Yip, Kay-Pong et al. (2006) Interactions between TGF-dependent and myogenic oscillations in tubular pressure and whole kidney blood flow in both SDR and SHR. Am J Physiol Renal Physiol 290:F720-32
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