The overall goal of this proposal is to understand the molecular mechanisms that govern differential regulation of the type-1 angiotensin II (AT1) receptor expression in specific segments of the nephron in response to altered sodium intake. This work is important because sodium-induced changes in circulating and local levels of Ang II and expression of its receptor play a major role in the regulation of sodium and water homeostasis and arterial pressure through their effects on glomerular hemodynamics and tubular ion reabsorption. On the basis of recent data collected in the P.I.'s laboratory and work by others, she will test the hypothesis that dietary sodium intake regulates expression of the functional AT1 receptor in the kidney in a segment specific manner through activation of one or more signaling pathways by the renin-angiotensin system and/or sympathetic nervous system. This hypothesis will be tested by using an integrated approach examining: (1 In vivo: The effects of altered dietary sodium intake on AT1 receptor mRNA levels and AT1 receptor binding and affinity in glomerular mesangial cells, proximal tubules, and medullary thick ascending limbs of the loop of Henle (MTAL). Indices of functional coupling of AT1 receptors will include measurements of Ang II-induced changes in intracellular Ca2+ , cAMP levels, and cytochrome P450-dependent metabolites of arachidonic acid and (2) In vitro: Cultures of mesangial cells, proximal tubules and MTALs will be used to study the specific signaling pathways that mediate homologous and heterologous regulation of AT1 receptors induced by Ang II and norepinephrine. These experiments will be the first to provide a coordinated assessment of the molecular regulation of AT1 receptor expression in specific segments of the nephron, and will enable us to understand the control of AT1 receptor expression in the coordinated physiological adaptation to altered sodium intake. Moreover, these studies will provide a basis for understanding how a defective regulation of these systems may contribute to abnormalities in sodium and water balance and blood pressure regulation. The results of these experiments also may provide clues for the development of novel therapeutic agents that act selectively on specific pathways regulating AT1 receptor expression in specific segments of the nephron.
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