Twelfth Annual Grant Winners 2011-2012
Title: Molecular Effects of Angiotensin II on Astrocytes Isolated from Hypertensive Rats
Andres Malave, PhD (HPD-PHR)
Faculty and Students:
Michelle Clark, PhD (HPD-PHR)
Umadevi Kandalam, PhD (HPD-DEN)
Larisa Odessky, BS (HPD-PHARM)
Hieu Tran AA (HPD-PHR)
In the United States over 75 million people twenty or older suffer from hypertension (high blood pressure).
Hypertension causes insidious physiological changes leading to kidney disease, heart failure, heart attacks, and strokes.
According to the American Heart Association, the percentage of Americans with hypertension and the number of deaths
attributed to hypertension are increasing. Numerous anti-hypertensive medications are available, including those that
target angiotensin II synthesis and effects. However, treatment of hypertension has been unsuccessful because our
knowledge of the intracellular systems and cell types that control blood pressure are limited. This translated into 90-95%
of the causes of hypertension unknown. Angiotensin II, produced by the rennin angiotensin system (RAS), elicits
physiological effects that may lead to increases in blood pressure. Angiotensin II produced in the brain is involved with blood pressure regulation, and hyperactivity of this system may lead to hypertension. We propose to use astrocytes
prepared from the brains of spontaneously hypertensive rats (SHR) as a model brain system to determine whether
endogenous or stimulated changes in angiotensin converting enzyme-2 (ACE2) and angiotensinogen (RAS components)
contribute to hypertension in these animals. ACE2 and angiotensinogen may contribute to hypertension in diverse ways.
ACE2 produces angiotensin-(1-7) which counteracts angiotensin II blood pressure effects. Angiotensinogen is the
precursor molecule for angiotensin peptides. Changes in angiotensinogen levels determine the amount of angiotensin II
that will be produced. The specific aims of this project are to: 1) determine whether ACE2 activity, protein, and mRNA
levels are decreased in astrocytes isolated from SHR; and 2) determine whether angiotensinogen mRNA and protein
levels are increased in astrocytes isolated from SHR. It is essential that we understand how different cell types are affected
by a dysregulated RAS and how these cells regulate blood pressure to allow us to better prevent and treat hypertension.