The long-term goal of this proposed study is to identify the mechanisms of pressure natriuresis in proximal tubules and its relationship with hypertension. Pressure natriuresis is an increase of Na+ excretion caused by an increase in arterial pressure in the absence of changes in renal blood flow and glomerular filtration rate, which enables the kidney to use arterial pressure as an input signal to regulate the extracellular fluid volume. However, pressure natriuresis is set to higher blood pressure levels in all form of hypertension. An acute blood pressure increase inhibits fluid and NaC1 reabsorption in rate proximal tubules, and this response is associated with a rapid internalization of apical Na+/H+ exchangers from the brush border into subapical intracellular stores. This response probably contributes a large fraction of the natriuresis and diuresis that occurs when blood pressure rises. The objective of this proposal is to test whether trafficking of apical Na+/H+ exchangers induced by acute hypertension inhibits apical Na+/H+ exchangers activity and fluid reabsorption in proximal tubules in vivo, to delineate the mechanisms of this protein-trafficking process, and to probe the possible changers in hypertension. The rate of change in intracellular pH (dpHi/dt) upon luminal removal of Na+ in perfused proximal tubules in situ is used as a index of the activities of Na+/H+ exchangers. The intracellular pH is monitored with a dual pulse-lasers system designed to measure intracellular pH with minimum bleaching of BCECF, a pH sensitive fluorescence dye commonly-used to measure intracellular pH. Proximal fluid reabsorption is measured continuously with a non-obstructing optical technique developed in this laboratory. Confocal fluorescent microscopy and immunohistochemistry are employed to investigate the protein trafficking process triggered by acute hypertension. Spontaneously hypertensive rates (SHR) are used as an animal model of chronic hypertension. This proposed study will provide new information to understand the cellular mechanism of pressure natriuresis in proximal tubules, and the altered relationship between renal perfusion pressure and urinary Na+ excretion in hypertension. These may lead to a better understanding of the role of the kidney in hypertension, and possibly to new treatment principles.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiovascular and Renal Study Section (CVB)
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University of South Florida
Schools of Medicine
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Chon, Ki H; Raghavan, Ramakrishna; Chen, Yu-Ming et al. (2005) Interactions of TGF-dependent and myogenic oscillations in tubular pressure. Am J Physiol Renal Physiol 288:F298-307
Yip, Kay-Pong (2005) Flash photolysis of caged nitric oxide inhibits proximal tubular fluid reabsorption in free-flow nephron. Am J Physiol Regul Integr Comp Physiol 289:R620-R626
Walstead, Christopher; Yip, Kay-Pong (2004) Acute arterial hypertension inhibits proximal tubular fluid reabsorption in normotensive rat but not in SHR. Am J Physiol Regul Integr Comp Physiol 286:R726-33
Yip, Kay-Pong; Tsuruoka, Shuichi; Schwartz, George J et al. (2002) Apical H(+)/base transporters mediating bicarbonate absorption and pH(i) regulation in the OMCD. Am J Physiol Renal Physiol 283:F1098-104
Yip, Kay-Pong (2002) Coupling of vasopressin-induced intracellular Ca2+ mobilization and apical exocytosis in perfused rat kidney collecting duct. J Physiol 538:891-9
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
Yip, K P; Wagner, A J; Marsh, D J (2000) Detection of apical Na(+)/H(+) exchanger activity inhibition in proximal tubules induced by acute hypertension. Am J Physiol Regul Integr Comp Physiol 279:R1412-8
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