Hypertension affects more than 60 million people in the US, but the precise cause of elevated blood pressure cannot be determined in most affected individuals. Nonetheless, blockade of the renin-angiotensin system (RAS) lowers blood pressure in the majority of hypertensive patients, indicating a key causal role for the RAS in this disorder. The main actions of the RAS to control blood pressure are mediated by type I (AT1) angiotensin receptors. AT1 receptors are ubiquitously expressed and have myriad actions in every major organ system. Despite the widespread clinical use of RAS antagonists, the relative contributions of AT1 receptors in individual tissue compartments to the regulation of blood pressure has been difficult to dissect and quantify. A major objective of this program is to establish specific cellular targets of AT1 receptors that affect hypertension pathogenesis in order to: (1) define the mechanisms conferring the benefits of RAS blockade, which could be exploited to optimize treatment and (2) to identify final common pathways with significant potential to alter blood pressure, which could be promising therapeutic targets. Our studies in previous funding periods have provided fundamental advances in understanding how the RAS and its receptors affect blood pressure. Using kidney cross-transplantation, we previously showed that AT1 receptors inside the kidney play a dominant role in hypertension. Within the kidney, these receptors are expressed by epithelial cells and by vascular smooth muscle cells of the renal vasculature. At both of these sites, they can potentially affect salt excretion and thereby modulate blood pressure. In recent studies, we found that AT1 receptors in discrete sub-populations of the renal epithelium can alter blood pressure. However, the characteristics of these responses differ significantly between nephron segments, with very distinctive regulatory consequences. For example, AT1A receptors in the epithelium of the proximal tubule promote hypertension, whereas our preliminary studies suggest that in the collecting duct, they attenuate blood pressure elevation. Here we propose to precisely define the actions of AT1 receptors in the kidney that protect against hypertension. As such, new therapeutic strategies may emerge to preserve or augment protective pathways while at the same time maximally inhibiting those promoting increased blood pressure. To this end, we will pursue the following Specific Aims: (1) Define the contribution of AT1 receptors in the collecting duct to blood pressure homeostasis and hypertension pathogenesis. (2) Identify the mediators of resistance to hypertension linked to AT1 receptors in the collecting duct. (3) Determine the role of epithelial- vascular cross talk in regulation of blood pressure by AT1A receptors in the collecting duct.