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(Circulation Research. 2006;98:463.)
© 2006 American Heart Association, Inc.

Reviews

Angiotensin-Converting Enzyme II in the Heart and the Kidney

Ursula Danilczyk, Josef M. Penninger

From the IMBA, Institute for Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria.

Correspondence to J.M. Penninger, IMBA, Institute for Molecular Biotechnology of the Austrian Academy of Sciences, D. Bohr Gasse 7, A-1030 Vienna, Austria. E-mail josef.penninger{at}imba.oeaw.ac.at

This Review is part of a thematic series on Angiotensin Converting Enzyme, which includes the following articles:

Six Truisms Concerning ACE and the Renin-Angiotensin System Educed from the Genetic Analysis of Mice

ACE II in the Heart and the Kidney

Signaling by the Angiotensin Converting Enzyme

ACE Polymorphisms

ACE and Vascular Remodeling
Rudi Busse Editors

The renin-angiotensin system (RAS) has been recognized for many years as critical pathway for blood pressure control and kidney functions. Although most of the well-known cardiovascular and renal effects of RAS are attributed to angiotensin-converting enzyme (ACE), much less is known about the function of ACE2. Experiments using genetically modified mice and inhibitor studies have shown that ACE2 counterbalances the functions of ACE and that the balance between these two proteases determines local and systemic levels of RAS peptides such as angiotensin II and angiotensin1–7. Ace2 mutant mice exhibit progressive impairment of heart contractility at advanced ages, a phenotype that can be reverted by loss of ACE, suggesting that these enzymes directly control heart function. Moreover, ACE2 is also found to be upregulated in failing hearts. In the kidney, ACE2 protein levels are significantly decreased in hypertensive rats, suggesting a negative regulatory role of ACE2 in blood pressure control. Moreover, ACE2 expression is downregulated in the kidneys of diabetic and pregnant rats and ACE2 mutant mice develop late onset glomerulonephritis resembling diabetic nephropathy. Importantly, ACE2 not only controls angiotensin II levels but functions as a protease on additional molecular targets that could contribute to the observed in vivo phenotypes of ACE2 mutant mice. Thus, ACE2 seems to be a molecule that has protective roles in heart and kidney. The development of drugs that could activate ACE2 function would allow extending our treatment options in diabetic nephropathy, heart failure, or hypertension.

Key Words: angiotensin-converting enzyme 2 • knockout mice • renin-angiotensin system

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