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Overview of the renin-angiotensin system

Overview of the renin-angiotensin system
Literature review current through: Jan 2024.
This topic last updated: Sep 27, 2023.

INTRODUCTION — 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, 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.)

A teleological view holds that activation of the RAS was a critical adaptation for survival of mammals that migrated from sea to land, in defense against life-threatening circumstances like salt and water deprivation, diarrhea, or hemorrhage. While protective in its purpose, activation of the system in many patients today is maladaptive and leads to disease, with heart failure being a classic example. Sodium retention, coupled with hyperaldosteronism, results in vascular remodeling of the heart and disease progression [1].

Blockade of the RAS has represented a groundbreaking development in the prevention and treatment of heart failure, chronic kidney disease, myocardial infarction, and hypertension [2-8]. There are a number of steps at which the RAS can be interrupted. Beta-adrenergic blocking agents reduce renin release. ACE inhibitors block the conversion of angiotensin I to angiotensin II downstream from the renin step, and angiotensin receptor blockers (ARBs) interfere with the interaction of angiotensin II with its receptor. Mineralocorticoid receptor antagonists (MRAs) antagonize the action of aldosterone at its receptor. Another class of antihypertensive drugs, renin inhibitors, interfere with the first step in the cascade, which is the interaction of renin with its substrate, AGT.

Whether or not to block the RAS is no longer the appropriate question in the clinical scenarios of diabetic nephropathy, chronic kidney disease, and heart failure. Rather, efforts are dedicated to answering how best to optimize blockade. Discoveries of new peptides, enzymes, receptors, and cell-signaling targets of the system are changing our understanding of physiology and providing potential new therapeutic targets.

MAJOR COMPONENTS OF THE RAS — The main components of the RAS are discussed in the following sections.

Renin — The afferent arteriole of each glomerulus contains specialized cells called the juxtaglomerular cells (figure 2). These cells synthesize the precursor, prorenin, which is cleaved into the active proteolytic enzyme, renin. Active renin is then stored in and released from secretory granules [9,10]. Renin initiates a sequence of steps that begins with cleavage of the decapeptide, angiotensin I, from renin substrate (angiotensinogen [AGT]), an alpha-2-globulin produced in the liver (and other organs including the kidney) [11,12]. This first step is also the rate-limiting step of the RAS cascade. Renal hypoperfusion, caused by hypotension or volume depletion, and increased sympathetic activity are the major physiologic stimuli to renin secretion (figure 3).

Control of renin secretion — Factors that regulate renin secretion are related to the classical actions of angiotensin II: increased sodium and water reabsorption; and systemic vasoconstriction. Short-term feedback of renin secretion is mediated via angiotensin II; angiotensin II binds to its receptor to inhibit renin gene expression [13]. Long-term feedback of renin secretion is mediated by the physiologic cycle of angiotensin II; angiotensin II increases blood pressure and sodium retention, which then inhibits renin release.

The changes in extracellular fluid volume that govern renin release are primarily sensed at three sites (figure 3) [9]:

Baroreceptors (or stretch receptors) in the wall of the afferent arteriole [14]

Cardiac and arterial baroreceptors, which regulate sympathetic neural activity and the level of circulating catecholamines, both of which enhance renin secretion via the beta-1-adrenergic receptors [15,16]

The cells of the macula densa in the early distal tubule (figure 2), which sense changes in luminal fluid sodium chloride concentration and are involved in signaling pathways that control renal hemodynamics, glomerular filtration, and renin release [17-19]

In normal subjects, the major determinant of renin secretion is sodium intake: a high intake expands the extracellular fluid volume and decreases renin release, whereas a low sodium intake (or sodium and water losses from any site) leads to a reduction in extracellular fluid volume and stimulation of renin secretion. Acute increases in renin secretion, such as those occurring with hypovolemia, primarily reflect the release of preformed renin from intracellular secretory granules [10]. Chronic, persistent stimuli to renin release lead to increased synthesis of new prorenin and renin [10].

Increases in renin secretion produce increases in angiotensin II and aldosterone production, sodium reabsorption, and expansion of the extracellular fluid volume. By contrast, decreases in renin secretion produce decreases in angiotensin II and aldosterone production, sodium reabsorption, and reduction of the extracellular fluid volume. Intrarenal formation of angiotensin II probably plays at least a contributory role in the sodium retention induced by renin, as illustrated by the rise in messenger RNA for both renin and angiotensin substrate in the renal cortex following a low-sodium diet [20]. (See 'Tissue renin-angiotensin systems' below.)

Measurement of renin — Circulating renin is measured indirectly or directly. Measurement of renin in the context of adrenal disease is presented in detail elsewhere (see "Assays of the renin-angiotensin-aldosterone system in adrenal disease"):

The plasma renin activity (PRA) is an indirect measure of renin that employs an enzyme-kinetic bioassay, which measures its capacity to generate angiotensin I. The rate of angiotensin I production, and therefore PRA, is critically dependent upon the concentration of substrate in plasma (ie, AGT).

The plasma renin concentration (PRC) employs a direct immunosorbent assay that measures the number of active renin molecules, both prorenin and renin [21]. This assay is easier to perform and more suited for automated testing.

The question of which measure is more clinically meaningful is debated. Under normal physiologic conditions, there is good correlation between PRA and PRC, so long as the AGT concentration is constant. In pregnancy and in women taking oral contraceptive pills, an increase in AGT results in higher PRA than PRC, while in patients with severe heart failure, low AGT concentrations result in lower PRA values [22].

The value of measuring renin in pathologic states such as hypertension has been studied extensively. As an example, renin is frequently measured in patients suspected of having primary aldosteronism. (See "Diagnosis of primary aldosteronism", section on 'Case detection'.)

By contrast, the usefulness of measuring renin in patients with primary (formerly, "essential") hypertension is less clear. One theory holds that, in hypertensive patients with elevated renin levels, the hypertension is caused by arteriolar vasoconstriction, while in patients with low renin levels, the hypertension is caused by expansion of the extracellular fluid volume [23]. This theory led to a proposal whereby treatment could be individualized based upon renin levels [24]. However, due to large variations in plasma renin measurements and in clinical responses to therapy, renin levels are not typically measured in patients with primary hypertension to guide therapy, except if screening for primary aldosteronism.

Inhibition of renin — Renin was an attractive target for blockade of the RAS because it operates at the rate-limiting step (namely, the conversion of AGT to angiotensin I) and because renin is highly specific for its substrate [25]. In addition, both angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) produce a reactive renin rise and, therefore, an increase in angiotensin peptides (angiotensin I increases with ACE inhibitors, and both angiotensin I and angiotensin II increase with ARBs). Only renin inhibition renders the RAS quiescent, suppressing all of the angiotensin products.

However, this effect has not translated into a clear clinical advantage [26]. Although aliskiren (the sole available renin inhibitor) is effective and safe as a single antihypertensive agent, it should not be combined with an ACE inhibitor or ARB [27]. Combination RAS blockade does not improve outcomes in most patients and increases adverse events. As a result, it is unlikely that renin inhibitors will gain a place in routine clinical care without favorable hard endpoint studies in nondiabetic kidney disease [28]. Recommendations to not use dual RAS blockade are presented in detail elsewhere:

(See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Combination of ACE inhibitors and ARBs'.)

(See "Major side effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers", section on 'Combination of ACE inhibitors and ARBs'.)

(See "Treatment of hypertension in patients with diabetes mellitus", section on 'Avoid combination renin-angiotensin system inhibition'.)

(See "Renin-angiotensin system inhibition in the treatment of hypertension", section on 'ACE inhibitors plus ARBs'.)

(See "Treatment of diabetic kidney disease".)

Prorenin — Prorenin is constitutively expressed and is also secreted into the systemic circulation [10]. Despite its abundance, the physiological role of prorenin remains unclear, as no direct effect on systemic hemodynamics has been shown. In most individuals, prorenin accounts for up to 90 percent of circulating renin, while active renin accounts for 10 percent. However, in patients with longstanding diabetes, prorenin is greatly elevated and active renin is normal or low, such that 99 percent or more of circulating renin is prorenin. Higher levels of prorenin in patients with diabetes is associated with albuminuria, nephropathy, and diabetic retinopathy [29,30]. One study, for example, found that a rise in prorenin concentration among patients with diabetes independently predicted the subsequent onset of albuminuria [31]. The physiologic effects of prorenin in patients with diabetes are unknown.

Prorenin may be important for uterine function, particularly during pregnancy [32]. In addition to an intrauterine tissue RAS, an ovarian as well as a fetal RAS are also involved in normal pregnancy. These tissue systems appear to play key roles in ovulation, implantation, placentation, and development of the uteroplacental and umbilicoplacental circulations [33].

(Pro)renin receptor — The existence of the (pro)renin receptor (PRR), a receptor for both prorenin and renin, was suspected based upon evidence demonstrating effects of renin that were independent of angiotensin II, and it was finally identified in 2002 [34]. Binding of renin to the PRR causes a fourfold increase in the ability of renin to catalyze the conversion of AGT to angiotensin I. When bound to the PRR, prorenin undergoes a conformational change that uncovers its active catalytic site, and therefore, prorenin can function as enzymatically active renin when bound to the receptor. In addition, binding of prorenin or renin to the PRR activates various signaling pathways, including the mitogen-activated protein kinases (MAPKs), extracellular signal-regulated (ERK) 1 and 2, transforming growth factor beta 1, and plasminogen activator inhibitor-1 (PAI-1).

The PRR is an aspartyl protease (the first such protease discovered). The receptor is abundantly expressed in the heart, brain, placenta, and eye, with lesser expression in the liver and kidney. Within the kidney, the receptor is localized in the mesangium of glomeruli and in the subendothelium of renal arteries, colocalizing with renin [35]. The existence of the PRR in the heart and kidney may help to explain the responsiveness of diabetic patients to RAS blockade despite low levels of active renin (and high levels of prorenin) [36]. However, prorenin concentrations in vivo are generally too low for the PRR to have an important role in the RAS, and therefore the importance of the PRR in cardiovascular or renal disease is uncertain [37,38].

This does not mean the PRR has no role. Functions of the PRR unrelated to the RAS have been demonstrated. Animal studies have shown the importance of the PRR in embryonic development and stem cell biology [37,39], and genetic ablation of PRR produces an embryonic-lethal phenotype [40].

Angiotensinogen — Angiotensinogen (AGT), synthesized mainly by the liver, is the sole substrate for renin. The cleavage of AGT by renin represents the rate-limiting step in the enzyme cascade that makes up the classic circulating RAS. AGT may also be produced in the brain, large arteries, kidney, adrenal glands, and adipose tissues [41], although the liver is the main source of AGT [42]. AGT is regulated by several hormones. Both oral estrogens and glucocorticoids stimulate AGT synthesis, but it is unknown whether this upregulation plays a major role in AGT activity [43,44]. AGT gene variants appear to have a modest effect on blood pressure and are considered susceptibility alleles in some populations.

Angiotensin-converting enzyme — The enzyme called angiotensin-converting enzyme (ACE) catalyzes the conversion of the decapeptide, angiotensin I, to the octapeptide, angiotensin II. This conversion occurs most extensively in the lung by ACE generated in vascular endothelial cells; ACE is also located in the glomerulus as well as many other tissues [45,46]. Thus, the pleiotropic effects of pharmacologic ACE inhibition may be due in part to inhibition of local, tissue ACE, in addition to inhibition of ACE in the lung. However, the clinical significance of ACE inhibition in different tissues is unknown [47].

ACE inhibitors were first developed by coincidence when scientists were searching for an explanation for hypotension induced by the venom of a pit viper [48]. The theory that a stimulator of bradykinin metabolism might also be an inhibitor of ACE, since both substrates are cleaved by a peptidyl-dipeptide hydrolase, proved to be correct. ACE is a nonspecific enzyme, also acting as a kininase; ACE inhibitors therefore result in the accumulation of bradykinin, which is thought to be responsible for the cough sometimes caused by these drugs [49]. (See "Major side effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers", section on 'Cough'.)

As a class, ACE inhibitors have proven antihypertensive and antiproteinuric effects, and they delay progression of renal disease. Some experts believe that their efficacy is due both to reduction of plasma angiotensin II levels and also the concomitant increase in plasma bradykinin levels [50]. (See "Renin-angiotensin system inhibition in the treatment of hypertension" and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Renin-angiotensin system inhibitors' and "Treatment of hypertension in patients with diabetes mellitus".)

Angiotensin-converting enzyme 2 — A homolog to ACE has been identified and named angiotensin-converting enzyme 2 (ACE2) [51-53]. ACE2 is predominantly expressed in the endothelium of the coronary and intrarenal vessels and in the epithelium of the renal tubules [51]. ACE2 cleaves an amino acid from angiotensin I to form angiotensin (1-9) and cleaves an amino acid from angiotensin II to form angiotensin (1-7) [54]. A main action of the vasodepressor angiotensin (1-7) is activation of the Mas receptor, inducing kinases that lead to activation of endothelial nitric oxide synthase [55,56]. Thus, the ACE2/Mas pathway regulates opposing physiology to ACE and angiotensin II; however, the physiologic significance or any therapeutic potential of activating the ACE2/Mas pathway remains to be elucidated.

ACE2 has been identified as a specific receptor for the SARS-CoV-2 virus and the entry point for the virus into host alveolar cells. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Virology'.)

Angiotensin II — The classical systemic effects of angiotensin II include:

Vasoconstriction – Angiotensin II produces arteriolar vasoconstriction, which increases systemic vascular resistance and, therefore, systemic blood pressure.

Reabsorption of sodium and water – Angiotensin II stimulates sodium reabsorption directly in the proximal tubule [57-59], and indirectly in the cortical collecting tubule by inducing secretion of aldosterone by the adrenal cortex.

Both of these actions tend to reverse the hypotension or hypovolemia that is usually responsible for the stimulation of renin secretion (figure 3) [57]. In addition to influencing systemic hemodynamics, angiotensin II has an important role in the regulation of glomerular filtration rate (GFR) and renal blood flow [57]. Angiotensin II produces vasoconstriction of the efferent and afferent glomerular arterioles as well as the interlobular artery [60-62]. The net effect is a reduction in renal blood flow (due to the increase in renal vascular resistance) and an elevation in the hydraulic pressure in the glomerular capillary, which tends to maintain the GFR when the RAS is activated by a fall in systemic pressure.

Beyond these effects, however, angiotensin II has a host of important and mostly deleterious actions [63], as examples:

Angiotensin II acts as an inflammatory mediator through a variety of mechanisms, including intercellular and vascular adhesion molecules (ICAM and VCAM), reactive oxygen species, nuclear factor-kB, and superoxide [64-67], exerting a proinflammatory effect on leukocytes, endothelial cells, and vascular smooth-muscle cells.

Angiotensin II also provides a mitogenic stimulus for vascular smooth-muscle cells and promotes cellular proliferation, which could contribute to atherogenesis, and may also contribute to insulin resistance [63].

The effects of angiotensin II are mediated by binding to two specific angiotensin II receptors: the angiotensin II type 1 receptor (AT1R) and the angiotensin II type 2 receptor (AT2R) [68]. The majority of its actions, including the classical effects of vasoconstriction, stimulation of aldosterone release, and increased renal tubular sodium reabsorption, as well as many deleterious effects including fibrosis and inflammation, are mediated by the AT1R [68-70]. In addition, the "short feedback loop" is activated when angiotensin II inhibits the secretion of renin release via the AT1R on juxtaglomerular cells.

ARBs inhibit the binding of angiotensin II to AT1R, and it was originally assumed that their efficacy would exceed that of ACE inhibition because, in addition to blocking angiotensin II action generated by ACE, they inhibit the action of angiotensin II formed by other converting enzymes, including chymase. ARBs also result in higher levels of circulating angiotensin II, which, theoretically, could stimulate vasodilation and natriuresis via the AT2R, thereby enhancing the antihypertensive effect [50,71]. However, superiority to ACE inhibition has not been convincingly demonstrated. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults" and "Treatment of hypertension in patients with diabetes mellitus" and "Choice of drug therapy in primary (essential) hypertension".)

The AT2R is present in multiple sites within the kidney. The angiotensin II degradation peptide known as angiotensin III (des-aspartyl[1]-Ang II) has also been shown to activate the AT2R, likely acting as the main agonist of this receptor in the kidney and contributing to the counter-regulatory pathways that oppose the deleterious actions of angiotensin II (figure 1) [55,72]. Effects of angiotensin II and angiotensin III binding to the AT2R generally counteract its classical actions, producing vasodilation and natriuresis and possibly protecting against hypertension target-organ damage. AT2Rs are more sparsely expressed after fetal life but can be upregulated in response to injury [71,73-75]. Thus, like the angiotensin (1-7) Mas receptor and alamandine (an angiotensin peptide with an alanine rather than aspartate at the amino terminal), the AT2 receptor forms part of the protective RAS [76].

Aldosterone — Aldosterone, an adrenal steroid hormone, affects multiple tissues and plays an important role in renal and cardiovascular diseases. Angiotensin II is the most powerful stimulus for adrenal aldosterone secretion, mediated via AT1R in the adrenal cortex [77]. In addition to circulating angiotensin II, local production of angiotensin II occurs in the adrenal gland and contributes to aldosterone release [78]. Both adrenocorticotropic hormone (ACTH) and potassium also stimulate aldosterone secretion. (See "Adrenal steroid biosynthesis".)

Aldosterone binds to the mineralocorticoid receptor in various tissues, inducing pleiotropic effects. Its main action is in the kidney, where it increases the expression of epithelial sodium channels in the distal tubule, resulting in sodium and water reabsorption and potassium secretion (figure 4). These renal actions contribute to extracellular fluid volume expansion, increased blood pressure, decreased serum potassium, and, when aldosterone is produced in excess, primary aldosteronism. The hypokalemia that sometimes marks this syndrome results from aldosterone increasing potassium excretion in urine, feces, sweat, and saliva [79]. (See "Pathophysiology and clinical features of primary aldosteronism".)

Cortisol, which is present in substantially higher concentrations in the body than aldosterone, can also bind and activate the mineralocorticoid receptor in the kidney. However, 11-betahydroxysteroid dehydrogenase converts cortisol to cortisone, which cannot bind and activate the mineralocorticoid receptor. If this enzyme is inactivated by genetic mutation or the excess consumption of licorice, then a syndrome mimicking primary aldosteronism can result. (See "Apparent mineralocorticoid excess syndromes (including chronic licorice ingestion)".)

In addition to the collecting duct of the kidney, aldosterone has pleiotropic actions, primarily in the heart, vascular smooth muscle cells, and kidney, which may be mediated in part by autocrine and paracrine effects from local aldosterone production. Aldosterone acts on local mineralocorticoid receptors where it promotes generally deleterious effects, including inflammation, fibrosis, and, in certain clinical scenarios, neovascularization [80,81]. As an example, aldosterone synthase messenger RNA has been identified in endothelial and vascular smooth-muscle cells in the heart and blood vessels [82,83]. Pleiotropic actions include: activation of an inflammatory cascade and suppression of nitric oxide synthesis in the heart, leading to cardiac fibrosis [84-88]; sodium-dependent hypertrophy and hyperplasia of distal and collecting tubule cells [89,90]; and increased production of proinflammatory cytokines and reduced expression of insulin-sensitizing factors by adipocytes and preadipocytes [91], potentially contributing to insulin resistance [92-94]. Human studies have revealed associations of higher aldosterone levels with hypertension, central obesity, metabolic syndrome, glucose intolerance, hyperlipidemia, chronic kidney disease, atrial fibrillation, left ventricular hypertrophy, and heart failure [1,95-98].

Drugs that inhibit the action of aldosterone (mineralocorticoid receptor antagonists) are effective in a variety of disorders:

Heart failure – Mineralocorticoid receptor antagonists improve outcomes in patients with heart failure, including those with reduced ejection fraction and preserved ejection fraction. (See "Treatment and prognosis of heart failure with preserved ejection fraction" and "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Mineralocorticoid receptor antagonist'.)  

Hypertension, particularly resistant hypertension – Mineralocorticoid receptor antagonists can substantially lower blood pressure in patients with resistant hypertension, even in those without confirmed primary aldosteronism. (See "Treatment of resistant hypertension".)

Diabetic patients with acute myocardial infarction – Mineralocorticoid receptor antagonists are frequently given to diabetic patients who have suffered an acute myocardial infarction if the ejection fraction is low, even if symptomatic heart failure is absent. (See "Acute myocardial infarction: Patients with diabetes mellitus".)

Cirrhosis and ascites – Mineralocorticoid receptor antagonists are often used as a diuretic to treat ascites in patients with cirrhosis. (See "Ascites in adults with cirrhosis: Initial therapy".)

TISSUE RENIN-ANGIOTENSIN SYSTEMS — The concentration of angiotensin-converting enzyme (ACE) is highest in the lung, and it had long been thought that most angiotensin II formation occurred in the pulmonary circulation. Evidence for multiple extrarenal renin-angiotensin systems has been reported, demonstrating the synthesis of angiotensin II at a wide variety of sites, including the kidney, vascular endothelium, adrenal gland, heart, adipose tissue, gonads, placenta, liver, and, possibly, the brain [11,78,99-101]. These local, tissue systems may account for the persistent, although low, plasma levels of angiotensin II in anephric subjects [102]. In addition, tissue renin-angiotensin systems are likely involved in cardiovascular regulation and other functions ranging from cognition to ovulation [103].

While some components of the RAS are expressed locally, including ACE, AT1 and AT2, and the mineralocorticoid receptor, renin has never been demonstrated to be produced anywhere but the kidney, and the liver is considered the primary source for angiotensinogen (AGT) [104].

While some angiotensin II present in tissues originates from plasma, much of tissue angiotensin II likely originates from in situ produced angiotensin I [105,106]. Local angiotensin II production is important for the regulation of local processes. Major tissue renin-angiotensin systems capable of local angiotensin II generation include:

Kidney – Clinically, the most important and best described local, tissue RAS lies in the kidney. Both mRNA and proteins for all components of the RAS have been found in specific sites within the kidney [107], and various factors may regulate the intrarenal RAS [108]. Hypovolemia, for example, leads to an increase in renal messenger RNA expression for both renin (in the glomerulus) and AGT (in the proximal tubule) [109]. The proximal tubule also contains ACE and angiotensin II receptors, suggesting that local angiotensin II formation can occur and stimulate sodium reabsorption [110]. The observation that the concentration of angiotensin II in renal interstitial fluid is approximately 1000 times higher than in the systemic circulation is consistent with a local effect [111]. In addition, intrarenal angiotensin II is much more responsive than circulating angiotensin II to sodium intake [71,112,113]. These local effects could explain why ACE inhibitors are useful antihypertensive agents, even in patients with low plasma renin activity (PRA) and low circulating levels of angiotensin II [100,114]. Similarly, animals that lack renal ACE are not able to produce angiotensin II locally and are protected against hypertension [115]. Unlike the conventional circulating RAS, the local intrarenal RAS can auto-amplify angiotensin II production, providing a continual source of the peptide to maintain vasoconstriction, antinatriuresis, and hypertension [116].

Vascular endothelium – Local generation of angiotensin II also can occur in vascular endothelium, where it likely influences vascular tone and the development of hypertension [11,117]. As an example, hypovolemia increases AGT messenger RNA levels in aortic smooth muscle. If this results in enhanced release of AGT, then either locally produced or systemic renin could initiate the sequential formation of angiotensin I and, via endothelial ACE, angiotensin II. In addition, there is evidence supporting a role for the vascular tissue RAS in endothelial dysfunction and in arterial stiffness, which are seen in pathologic states including obesity, metabolic syndrome, and diabetes [118].

Heart – Multiple components of the RAS are synthesized locally in the heart, although the importance of these tissue-derived hormones in cardiac pathology is not completely understood. However, clinical studies have unequivocally demonstrated the efficacy of agents that block the RAS in preventing heart failure and recurrent myocardial infarction [119].

Central nervous system – Some components of the RAS have been identified within the brain [120], leading to the hypothesis that a local RAS contributes to various disorders including Alzheimer disease, Parkinson disease, stroke, epilepsy, and multiple sclerosis. In stroke, for example, a cerebroprotective pathway may be mediated by brain angiotensin-converting enzyme 2 (ACE2), local generation of angiotensin (1-7), and signaling through Mas [121,122]. However, clear evidence for independent angiotensin synthesis in the brain is lacking [101].

Measures of tissue RAS — One clinical consequence of the existence of tissue RAS is that measurement of the systemic RAS (ie, PRA or circulating angiotensin II) can provide a misleading estimate of the tissue RAS activity. Circulating renin measures may correlate poorly with the activity of tissue renin-angiotensin systems. In some patients with primary (formerly, "essential") hypertension, for example, angiotensin II appears to be responsible for persistent renal vasoconstriction and sodium retention, even though plasma levels of renin and angiotensin II are similar to those in hypertensive patients with normal renal perfusion [123]. These findings suggest that there can be a selective increase in the activity of the tissue RAS in the kidney. A similar selective activation of the tissue RAS in the kidney may occur in stable heart failure [12], in diabetic nephropathy, and may explain racial differences in renal hemodynamics [124].

There is no known way to obtain direct measures of tissue renin (or angiotensin II) in humans. Alternative (indirect) approaches to assessing tissue RAS are therefore required.

Indirect measurement of tissue RAS in the kidney is possible because there is substantial variation in angiotensin-mediated control of the renal circulation, and this can be ascertained by identifying variations in the renal vasodilator responses to captopril or vasoconstrictor responses to angiotensin II [125]. As an example, healthy Black individuals compared with White individuals have a blunted increase in renal plasma flow when switching from a low-salt to high-salt diet, have a blunted decrease in renal plasma flow when administered angiotensin II, and have a marked increase in renal plasma flow when given an ACE inhibitor; this phenotype suggests that angiotensin II levels in the kidneys of these individuals are increased [124]. This activated tissue RAS in the kidneys could sequentially produce increased sodium and water reabsorption, expansion of the extracellular fluid volume, and reduced circulating plasma renin levels (ie, a "low-renin" state). As with diabetes, the apparent low-renin state in Black individuals may indeed be paradoxical, reflecting activation of the RAS locally in the kidney as well as other tissues [36].

The interaction between the RAS and prostaglandins may seem confusing since each stimulates the secretion of the other [15,126-128] and since they induce opposing vascular actions (vasoconstriction with angiotensin II and vasodilation with most prostaglandins). However, angiotensin II is a systemic vasoconstrictor, whereas the prostaglandins act locally because they are rapidly metabolized when they enter the systemic circulation. Thus, the net effect of simultaneous renal secretion of angiotensin II and prostaglandins is that angiotensin II can cause systemic vasoconstriction and raise the blood pressure, while the prostaglandins minimize the degree of renal vasoconstriction, thereby maintaining renal blood flow and glomerular filtration rate (GFR) [127].

Finally, in addition to support for a local RAS active within tissues, accumulating data support the existence of an intracellular RAS and for "intracrine" (within-cell) actions of angiotensin II. The existence and biological importance of intracellular RAS within humans remains to be proven. Intracrine systems are proposed to work within multiple tissues and to be involved in the pathophysiology of conditions ranging from cardiac myocyte apoptosis to diabetic kidney disease [129].

SUMMARY

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. 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). 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, there are also several tissue (local) renin-angiotensin systems with autocrine and paracrine effects that function independently of each other and of the circulating RAS. (See 'Introduction' above.)

The main components of the RAS are (figure 1) (see 'Major components of the RAS' above):

Renin is synthesized from the precursor, prorenin, in juxtaglomerular cells (figure 2). Active renin is stored in and released from secretory granules and then cleaves the decapeptide, angiotensin I, from renin substrate (AGT). Renal hypoperfusion, caused by hypotension or volume depletion, and increased sympathetic activity are the major physiologic stimuli to renin secretion (figure 3). Circulating renin can be measured indirectly or directly; such measurements are most often used in screening for primary aldosteronism. (See 'Renin' above.)

Prorenin, the precursor of renin, is constitutively expressed and is also secreted into the systemic circulation. Despite its abundance, the physiological role of prorenin remains unclear. (See 'Prorenin' above.)

The (pro)renin receptor (PRR) is a receptor for both prorenin and renin. When bound to the PRR, the ability of renin to catalyze the conversion of AGT to angiotensin I is increased fourfold. When prorenin binds to the PRR, it undergoes a conformational change that uncovers its active catalytic site, permitting prorenin to function as enzymatically active renin. In addition, binding of prorenin or renin to the PRR activates various signaling pathways. However, an important physiologic role for the PRR in blood pressure regulation is uncertain. (See '(Pro)renin receptor' above.)

AGT is the sole substrate for renin. The liver is the main source of AGT production. (See 'Angiotensinogen' above.)

ACE catalyzes the conversion of the decapeptide, angiotensin I, to the octapeptide, angiotensin II. This conversion occurs most extensively in the lung by ACE generated in vascular endothelial cells; ACE is also located in the glomerulus as well as other tissues. Thus, the pleiotropic effects of pharmacologic ACE inhibition may be due in part to inhibition of local, tissue ACE, in addition to inhibition of ACE in the lung. A homolog to ACE has been identified and named angiotensin-converting enzyme 2 (ACE2). ACE2 cleaves an amino acid from angiotensin II, forming angiotensin (1-7), which regulates a pathway that has opposing physiology to ACE and angiotensin II. (See 'Angiotensin-converting enzyme' above.)

Angiotensin II effects include arteriolar vasoconstriction and sodium reabsorption by the kidney. Both of these actions tend to reverse the hypotension or hypovolemia that is usually responsible for the stimulation of renin secretion (figure 3). Beyond these effects, however, angiotensin II has a host of important and mostly deleterious actions. The vast majority of these effects are mediated by the angiotensin II type 1 receptor (AT1R). Angiotensin II and angiotensin III binding to the sparsely expressed angiotensin II type 2 receptor (AT2R) have effects that generally counteract its classical actions, producing vasodilation and natriuresis. (See 'Angiotensin II' above.)

Aldosterone, an adrenal steroid hormone, binds to the mineralocorticoid receptor in various tissues, inducing pleiotropic effects in the kidney (where it increases sodium and water reabsorption and potassium secretion (figure 4)), the heart, and elsewhere. 'Aldosterone' above

Extrarenal renin-angiotensin systems exist and are likely to have important functions. Angiotensin II can be synthesized at a variety of sites, such as the kidney, vascular endothelium, adrenal gland, and heart. These local renin-angiotensin systems are likely involved in renal sodium handling, cardiovascular regulation, and other functions ranging from cognition to ovulation. (See 'Tissue renin-angiotensin systems' above.)

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Topic 98877 Version 11.0

References

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