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Overview of the renin-angiotensin system

Naomi DL Fisher, MD
Section Editor
George L Bakris, MD
Deputy Editor
John P Forman, MD, MSc


The renin-angiotensin system (RAS) plays a crucial role in the regulation of renal, cardiac, and vascular physiology, and its activation is central to many common pathologic conditions including hypertension, heart failure, and renal disease.

An overview of the normal function of the system, as well as ramifications of its dysfunction (overactivity) and potentials for therapeutic blockade, is provided here. Discussions of drugs that inhibit the RAS for the treatment of hypertension, kidney disease, and heart disease are provided in other topics.

The classical (historical) view of the RAS pathway begins with renin cleaving its substrate, angiotensinogen (AGT), to produce the inactive peptide, angiotensin I, which is then converted to angiotensin II by endothelial angiotensin-converting enzyme (ACE). ACE activation of angiotensin II occurs most extensively in the lung (figure 1). Angiotensin II mediates vasoconstriction as well as aldosterone release from the adrenal gland, resulting in sodium retention and increased blood pressure.

However, it is widely recognized that this classical view of the endocrine RAS pathway represents an incomplete description of the system. Instead of one simple circulating RAS, it is recognized that there are also several tissue (local) renin-angiotensin systems that function independently of each other and of the circulating RAS. In particular, angiotensin II generation at the tissue level by these local systems appears to have physiologic effects that are as important as circulating angiotensin II and, under some circumstances, more important than circulating angiotensin II.

Thus, the RAS includes local systems with autocrine (cell-to-same cell) and paracrine (cell-to-different cell) effects in addition to the classical circulating RAS with endocrine effects. Physiology of the RAS is proving far more complex than a simple circulating pathway controlling blood volume and blood pressure. In these local systems, activation of angiotensin II results in harmful effects and target-organ damage that extend beyond vascular and renal hemodynamics to direct tissue actions, including tissue remodeling, endothelial dysfunction, and fibrosis. A more detailed review appears below. (See 'Tissue renin-angiotensin systems' below.)

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Literature review current through: Sep 2017. | This topic last updated: Nov 24, 2015.
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