The renin-angiotensin system regulates blood pressure and fluid homeostasis through effects mediated by specific receptors that are widely distributed. Molecular biological and pharmacological observations have confirmed the existence of two major subtypes of angiotensin II receptors: AT1 receptors that are highly sensitive to biphenylimidazoles (e.g. losartan), and AT2 receptors that are sensitive to tetrahydroimidopyridines (e.g. PD 123319). Abundant physiological and pharmacological data have been accumulated to substantiate the observation that the AT1 receptor mediates a majority of the known effects of Ang II. By contrast, much less is known about AT1 mediated effects, however, it is generally accepted that there is a """"""""yin yang"""""""" relationship. Functional data indicate that the AT2 receptor opposes the blood pressure elevation of the AT1 receptor and other cellular actions as well. Data is now accumulating that a major mechanism whereby the AT2 receptor regulates blood pressures is through its ability to facilitate Na excretion. The overall goal of the PPG is to elucidate cellular/molecular mechanisms important for the regulation of blood pressure through effects on ion transport. The central hypothesis is that the AT2 receptor in the proximal tubule is responsible for diminished salt and fluid reabsorption that is observe in high physiological concentrations of angiotensin II. To test this hypothesis, we have assembled three projects that are directed at gaining a better understanding of structural/functional aspects of angiotensin receptors and cellular signaling pathways with influences on cytoskeleton and ion transporters in kidney epithelium. Attainment of this goal necessitates a multi- disciplinary group encompassing cell/organ physiology, molecular biology, biochemistry, pharmacology, biophysics and genetics. The program stresses a broad application to the problem of receptors, effectors, and coupling mechanisms to downstream targets employing cells and subcellular organelles and emphasizes and application of state- of-the-art techniques. Studies at a whole animal level will involve continuous infusions, assessments of blood pressure, and selective breeding of transgenic mice. Studies at a cellular level will utilize electrophysiology, fluorescent probes, pH measurement, and confocal microscopy. Studies at a molecular level involve cloning receptor subtypes, transfections of receptors (wild type and mutants), small G- protein (wild type and mutants), G-protein subunits and constitutively active and dominant negative mutants of phosphatases and kinases. Cores provide administrative support, tissue culture, animal models, biostatistics, and analytical instrumentation measures to enhance the scientific merit of all projects.
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