Key Regulator of Blood Pressure Identified in Mice
DURHAM, N.C. -- The lack of a single enzyme normally present in the kidneys can significantly elevate blood pressure in mice and may exert the same effect in some humans, according to a study led by researchers at Duke University Medical Center.
The enzyme, called angiotensin converting enzyme 2 (ACE2), appears to function in the kidneys to control blood pressure throughout the body, said the study's senior author, Thomas Coffman, M.D., chief of the Division of Nephrology. In the study, the researchers found that mice genetically lacking ACE2 had elevated blood pressure and enhanced susceptibility to hypertension.
"We've been able to demonstrate that the absence of ACE2 exacerbates the development of high blood pressure," Coffman said. "With more than 40 million people in the United States suffering from hypertension, this could prove to be a very significant finding."
Coffman cautioned, however, that it is not yet known whether the absence of ACE2 in people might contribute to hypertension.
ACE2 is structurally related to angiotensin converting enzyme (ACE). ACE generates the hormone angiotensin II (Ang II), which increases blood pressure by constricting blood vessels and causing fluid retention.
Overactivity of Ang II commonly contributes to high blood pressure in humans, Coffman said. The study suggests that ACE2 helps protect against hypertension by regulating the concentration of Ang II in the kidneys. ACE2 acts as a brake to counterbalance the actions of ACE and Ang II to increase blood pressure.
Understanding the relationships among ACE, ACE2 and Ang II could open new avenues for controlling blood pressure medically, Coffman said.
The researchers published their results in the August 2006 issue of the Journal of Clinical Investigation. The study was funded by the National Institutes of Health, the American Heart Association, the Department of Veterans Affairs and Millennium Pharmaceuticals.
For the study, researchers created mice in which the gene containing ACE2 was rendered inoperative or "knocked out." By comparing these ACE2-deficient mice with mice that had the ACE2 gene but were otherwise genetically identical, the scientists could be confident that any effects observed could be linked definitively to ACE2.
In their first experiment, the researchers briefly infused Ang II into ACE2-deficient mice to determine if and to what extent ACE2 contributes to the breakdown of Ang II. Levels of Ang II in blood turned out to be three times higher in the ACE2-deficient mice than in the control group, giving the researchers the first indication that ACE2 helps break down Ang II, said Susan Gurley, M.D., associate in medicine in the nephrology division and the paper's lead author.
Next, the researchers infused the mice with Ang II over two weeks to cause hypertension and to determine whether the absence of ACE2 might affect blood pressure levels. They found that blood pressure in ACE2-deficient mice rose significantly higher than in the control group. In addition, the level of Ang II recovered from the kidneys of the ACE2-deficient mice was six-fold greater than from mice in the control group.
According to Gurley, it currently is possible to determine the levels of ACE2 in humans by analyzing tissue, blood and urine samples. But physicians do not now conduct these tests in clinical settings, she said, adding that researchers are actively exploring how ACE2 levels might be correlated with human diseases such as hypertension.
Other researchers who participated in the study are Alicia Allred, Thu Le, and Robert Griffiths of Duke's nephrology division; Lan Mao and Howard Rockman of the cardiology division; Nisha Philip and Timothy Haystead of the pharmacology and cancer biology department; and Mary Donoghue, Roger Brietbart and Susan Acton of the cardiovascular biology department at Millennium Pharmaceuticals.