Dysregulation of AT, receptor in Transgenic Rats

DESCRIPTION (provided by applicant): The long-term goal of this project is to better understand the molecular mechanisms of blood pressure regulation, so that improved therapeutic interventions can be developed to treat hypertension. Hypertension is a major health problem in the United States where more than 50 million people (1 in 4 adults) have the condition. The consequences of chronic hypertension include damage to vital organs (such as kidney, lung, heart and brain) and either directly or indirectly contribute to more than 500,000 deaths annually in the U.S. Angiotensin II is a biologically active substance that triggers a myriad of responses in the body that may lead to hypertension. A hypertensive rat model will be used in this project in which a gene for one of the proteins implicated in blood pressure regulation- -renin- -has been overexpressed in the brain and blood vessels. These renin transgenic rats contain large amounts of this protein that results in an elevation of their blood pressure. Renin is one of the primary enzymes in the renin angiotensin system that is involved in the synthesis of angiotensin II. In the renin transgenic rats there is a chronic increase in angiotensin II in brain and blood vessels. This may cause numerous responses, but ultimately results in the elevation of blood pressure observed in these rats. In this research, cells and tissues will be isolated from the brain and blood vessels of normotensive and hypertensive rats and the renin-angiotensin system will be compared. Studies outlined in this proposal will determine whether the AT1 receptor is uncoupled from its corresponding G protein, leading to normal levels of receptors but an uncoupling of angiotensin II signaling such that the pathways leading to hypertension are selected. Studies will also be performed to determine whether associated tyrosine kinases and other intracellular signals of angiotensin II (for example, inositol phosphate production, mitogen activated protein kinases, transcription factors and others) are uncoupled from the AT1 receptor in the transgenic rats in the face of the chronic increase in angiotensin II. The findings of this proposal may result in better treatment strategies for hypertension caused by an increase level of endogenous angiotensin II, since studies are designed to determine whether effects of chronic elevation in angiotensin II can be overcome. Further, since in most cases the underlying causes of hypertension is not known, understanding how different types of cells are affected by long-term exposures to angiotensin molecules and how they in turn regulate blood pressure will allow for the design of better drugs for the prevention and treatment of hypertension.