The aim of the proposed project is to test the hypothesis that rats with genetic hypertension (SHR) and normotensive rats have differences in the dynamic characteristics of their tubuloglomerular feedback systems (TGF). TGF is an intrarenal control system that is important for the regulation of renal blood flow and the glomerular filtration rate, and therefore for salt and water excretion. We hypothesize that this difference leads to a change in the renal response to spontaneously occurring fluctuations in the arterial pressure, and therefore to a difference in the overall renal excretory function, which could be of significance in the development of high blood pressure. The hypothesis is based on the idea that the development of hypertension is always associated with a change in kidney function, especially the ability of the kidney to excrete salt in response to changes in the blood pressure. Earlier work has shown a difference in the dynamic properties of the TGF system present with hypertension. For example the hydrostatic pressure in the proximal tubule of the rat kidney oscillates with a well defined frequency around 30-50 mHz (2-3 cycles/min) in normotensive rats. These regular oscillations are not found in hypertensive rats. Instead the proximal pressure shows an irregular type of fluctuation, suggestive of a chaotic process. Since several studies have indicated that these oscillations are the result of the operation of the TGF system, the disappearance of the oscillatory pattern indicates that there are significant differences in the dynamic properties between the normal and the hypertensive rat strains. We propose to identify and quantify these differences in the TGF system experimentally, and to test the significance of these differences through computer simulation. Further, it has been shown that individual nephrons interact with each other. We therefore also propose to study, both experimentally and through computer simulation, the impact of this interaction on renal function. Using an integrative approach the proposed study will combine newly obtained data with previous data regarding both structure and function of the TGF system. Identifying differences in the dynamical characteristics in kidney function between normotensive and hypertensive rats may lead to a better understanding of the role of the kidney in hypertension, and possibly to new treatment principles.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29HL045623-02
Application #
3473349
Study Section
Cardiovascular and Renal Study Section (CVB)
Project Start
1991-08-01
Project End
1993-05-31
Budget Start
1992-08-01
Budget End
1993-05-31
Support Year
2
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Southern California
Department
Type
Schools of Medicine
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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Chan, W L; Holstein-Rathlou, N H; Yip, K P (2001) Integrin mobilizes intracellular Ca(2+) in renal vascular smooth muscle cells. Am J Physiol Cell Physiol 280:C593-603
Magyar, C E; Zhang, Y; Holstein-Rathlou, N H et al. (2000) Proximal tubule Na transporter responses are the same during acute and chronic hypertension. Am J Physiol Renal Physiol 279:F358-69
Marmarelis, V Z; Chon, K H; Holstein-Rathlou, N H et al. (1999) Nonlinear analysis of renal autoregulation in rats using principal dynamic modes. Ann Biomed Eng 27:23-31
Zhang, Y; Norian, J M; Magyar, C E et al. (1999) In vivo PTH provokes apical NHE3 and NaPi2 redistribution and Na-K-ATPase inhibition. Am J Physiol 276:F711-9
Zhang, Y B; Magyar, C E; Holstein-Rathlou, N H et al. (1998) The cytochrome P-450 inhibitor cobalt chloride prevents inhibition of renal Na,K-ATPase and redistribution of apical NHE-3 during acute hypertension. J Am Soc Nephrol 9:531-7
Chon, K H; Chen, Y M; Holstein-Rathlou, N H et al. (1998) Nonlinear system analysis of renal autoregulation in normotensive and hypertensive rats. IEEE Trans Biomed Eng 45:342-53
Zhang, Y; Magyar, C E; Norian, J M et al. (1998) Reversible effects of acute hypertension on proximal tubule sodium transporters. Am J Physiol 274:C1090-100
Chon, K H; Kanters, J K; Cohen, R J et al. (1997) Detection of chaotic determinism in time series from randomly forced maps. Physica D 99:471-86
Chon, K H; Korenberg, M J; Holstein-Rathlou, N H (1997) Application of fast orthogonal search to linear and nonlinear stochastic systems. Ann Biomed Eng 25:793-801

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