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Review
. 2012 Mar 15;302(6):H1219-30.
doi: 10.1152/ajpheart.00796.2011. Epub 2012 Jan 6.

The renin-angiotensin system: a target of and contributor to dyslipidemias, altered glucose homeostasis, and hypertension of the metabolic syndrome

Kelly Putnam  1 , Robin Shoemaker, Frederique Yiannikouris, Lisa A Cassis
Affiliations
Review

The renin-angiotensin system: a target of and contributor to dyslipidemias, altered glucose homeostasis, and hypertension of the metabolic syndrome

Kelly Putnam et al. Am J Physiol Heart Circ Physiol. .

Abstract

The renin-angiotensin system (RAS) is an important therapeutic target in the treatment of hypertension. Obesity has emerged as a primary contributor to essential hypertension in the United States and clusters with other metabolic disorders (hyperglycemia, hypertension, high triglycerides, low HDL cholesterol) defined within the metabolic syndrome. In addition to hypertension, RAS blockade may also serve as an effective treatment strategy to control impaired glucose and insulin tolerance and dyslipidemias in patients with the metabolic syndrome. Hyperglycemia, insulin resistance, and/or specific cholesterol metabolites have been demonstrated to activate components required for the synthesis [angiotensinogen, renin, angiotensin-converting enzyme (ACE)], degradation (ACE2), or responsiveness (angiotensin II type 1 receptors, Mas receptors) to angiotensin peptides in cell types (e.g., pancreatic islet cells, adipocytes, macrophages) that mediate specific disorders of the metabolic syndrome. An activated local RAS in these cell types may contribute to dysregulated function by promoting oxidative stress, apoptosis, and inflammation. This review will discuss data demonstrating the regulation of components of the RAS by cholesterol and its metabolites, glucose, and/or insulin in cell types implicated in disorders of the metabolic syndrome. In addition, we discuss data supporting a role for an activated local RAS in dyslipidemias and glucose intolerance/insulin resistance and the development of hypertension in the metabolic syndrome. Identification of an activated RAS as a common thread contributing to several disorders of the metabolic syndrome makes the use of angiotensin receptor blockers and ACE inhibitors an intriguing and novel option for multisymptom treatment.

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Figures

Fig. 1.
Fig. 1.
Components of the renin-angiotensin system (RAS). The precursor peptide, angiotensinogen, is cleaved by renin to form the decapeptide angiotensin I. The catalytic activity of renin increases when bound to the (pro)renin receptor [(P)RR], and furthermore, the otherwise inactive prorenin can become catalytically active when bound to the (P)RR. The dipeptidase angiotensin-converting enzyme (ACE) cleaves angiotensin I to form the octapeptide angiotensin II (ANG II), the central active component of this system. ANG II can be catabolized by angiotensin-converting enzyme 2 (ACE2) into angiotensin-(1–7) [ANG-(1–7)], another active peptide of this system which typically opposes the actions of ANG II. ANG II can also be cleaved into smaller fragments, such as angiotensin III and angiotensin IV by aminopeptidases A and M, respectively. Most effects of ANG II are mediated by the angiotensin type 1 receptor (AT1R); however, ANG II can also bind to the angiotensin type 2 receptor (AT2R), which generally exhibits opposing effects to those at the AT1R. ANG-(1–7) acts via the Mas receptor and angiotensin IV can bind to the insulin-regulated aminopeptidase receptors (IRAP).
Fig. 2.
Fig. 2.
Interplay between the RAS and the metabolic syndrome. Specific factors of the metabolic syndrome (hypercholesterolemia, hyperglycemia, obesity defined as elevated waist circumference) regulate the expression of components of the RAS that activate ANG II production and responsiveness in specific tissues/cell types. Regulated production, catabolism, or secretion of RAS components from pivotal cell types (smooth muscle cells, endothelial cells, adipocytes, pancreatic islet cells, kidney cells, brain cells) results in angiotensin peptide-mediated mechanisms that then augment or contribute to the development of specific aspects of the metabolic syndrome.
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