The actions of the renin-angiotensin system (RAS) to control blood pressure are primarily mediated by type 1 (AT1) angiotensin receptors. The key role of AT1 receptors in blood pressure homeostasis is highlighted by the phenotype of mice lacking the AT1A receptor, the major murine AT1 receptor isoform. We have previously shown that these animals have markedly reduced blood pressures and profound sodium sensitivity. As AT1 receptors are ubiquitously expressed and have myriad actions in every major organ system, it has been difficult in the intact animal to precisely dissect and quantify the contribution of AT1 receptors in individual tissue compartments to the regulation of blood pressure. In work done during the previous funding period using a cross-transplantation strategy, we showed that AT1A receptors in the kidney have unique, aldosterone-independent actions to determine the normal level of blood pressure. We hypothesize that these critical regulatory actions are mediated by AT1 receptors in specific renal epithelial lineages where they directly modulate sodium reabsorption. Our previous studies also showed that AT1A receptors outside the kidney make definitive and non-redundant contributions to blood pressure homeostasis and that the magnitude of this effect is similar to that of intra-renal AT1A receptors. We posit that this extra-renal control of blood pressure is primarily accomplished through regulation of vascular resistance by AT1 receptors in vascular smooth muscle cells. To test these hypotheses, we will develop novel mouse lines with deletion of AT1 receptors in specific nephron segments and in vascular smooth muscle cells. By determining the physiological consequences of interrupting AT1 receptor signaling in these circumscribed tissue compartments, we will identify the key cell lineages used by the RAS as a mechanism to control blood pressure. These studies have 3 specific aims: (1) To identify renal epithelia/cell lineages that are critical for the regulation of blood pressure by AT1 receptors, (2) To determine whether the actions of AT1 receptors in vascular smooth muscle cells are a major mechanism for chronic blood pressure control, (3) To define the role of renal AT1 receptors in the pathogenesis of hypertension.
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