Angiotensinogen and ACE2 Expression in Astrocytes of mRen2(27) Transgenic Rats

Grant Winner

  • Michelle Clark, Ph.D. – College of Pharmacy

Dean

  • Andres Malave – College of Pharmacy

Abstract

Hypertension is a major health problem in the United States contributing to more than 500,000 deaths annually. Angiotensin II (Ang II) is a biologically active octapeptide that triggers a myriad of physiological responses that may lead to hypertension. This project will use a hypertensive rat model known as the mRen2(27) transgenic rat to determine the effects of Ang II on hypertension. A hallmark of this rat model is an overactive renin-angiotensin system (RAS) with a central-mediated etiology. This overactive brain RAS, with augmented responses to Ang II, may arise from dysregulation of one of its many components, including the Ang II inactive precursor molecule "angiotensinogen", which is primarily synthesized in astrocytes. Further, angiotensin converting enzyme 2 (ACE2), a key enzyme of the RAS has been recently discovered. This enzyme is responsible for metabolizing any excess Ang II into angiotensin-(1-7), which are two peptides with opposite effects. Whether expression of ACE2 may be suppressed during hypertension, leading to increased levels of Ang II, is another possible mechanism by which the brain RAS system may become overactive.

In this proposal, the dysregulation of the brain RAS will be explored. In cultured rat cerebellar and brainstem astrocytes isolated from normotensive controls and mRen2(27) transgenic rat pups, the production of angiotensinogen and the expression of ACE2 will be measured. It is our hypothesis that angiotensinogen levels should be increased and the expression of ACE2 should be diminished in these rats. These changes would lead to increase levels of Ang II and an overactive RAS. In most cases, the underlying cause of hypertension is not known; therefore, understanding how different types of cells are affected by an overactive RAS and how they, in turn, regulate blood pressure will allow us to better prevent and treat hypertension.