Angiotensin receptor genes and blood pressure regulation

Duke University, Durham NC

Investigators

Linked publications & trials

Abstract

The actions of the renin-angiotensin system (RAS) to control blood pressure are primarily mediated by type I (ATd angiotensin receptors. In work done during the previous funding period using a kidney crosstransplantation model, we demonstrated distinct roles for pools of AT 1 receptors both in the kidney and in extra-renal tissues to determine the normal level of blood pressure. In hypertension on the other hand, we found that AT1 receptors in the kidney play the dominant role, whereas AT1 receptors outside the kidney have little impact. Accordingly, a major objective of the studies proposed here is to precisely localize key cellular targets of AT1 receptors within the kidney that control blood pressure. In order to determine the cell lineages mediating these powerful effects, we have generated mouse lines allowing deletion of AT1 receptors in specific cell populations using the Cre-Ioxp system. In our preliminary studies, we have identified a major contribution of AT1 receptors in epithelia of the proximal tubule to baseline control of blood pressure and to the pathogenesis of hypertension. We hypothesize that AT 1 receptors in proximal tubule modulate blood pressure by impacting sodium and fluid reabsorption through effects on: key sodium transporters, the intra-renal RAS, and oxidative stress pathways. We will test this hypothesis using unique mouse models developed under the auspices of this program. By establishing a hierarchy of physiological roles for distinct AT 1 receptor populations, we will define the cell lineages used by the RAS to control blood pressure and provide new insights into their underlying mechanisms.