The Renin–Angiotensin–Aldosterone System

Evolution to terrestrial life meant leaving behind the sea and its continuous source of salt and water. Water on land, when available, was fresh, and therefore adaptation to land necessitated the development of mechanisms to preserve salinity. An internal source of salinity is provided by extracellular fluid. Each arterial pulse of blood to exchange vessels of the microcirculation represents an onrushing saline tide that maintains a dynamic equilibrium with extracellular fluid. Animals living on land had to become capable of preserving their internal environment, including maintaining osmotic balance and salinity under a wide range of conditions over which they had little control. Kidneys became responsible for regulating the balance of salt and water7,8 by conserving both during periods of deprivation and excreting a dilute urine when water consumption was high. These adaptations required a concentrating and diluting mechanism and were accomplished with the appearance of the loop of Henle. Glomerular filtration in mammals would be maintained within a narrow range despite modifications in the volume and composition of the filtrate. Toward this end, kidneys require a plentiful supply of blood. Renal function is therefore dependent on an adequate cardiac output, of which 25 percent will normally be apportioned to the kidneys. This dependence of renal function on cardiac output explains the vulnerability of patients with heart failure to abnormal renal function, including reduced excretion of salt and water. In heart failure, a competition arises between organs for reduced systemic blood flow. It is particularly evident during exercise, when the vasodilation that appears in working skeletal muscle deprives the kidneys of some of their accustomed blood flow.

Normal regulation of salt and water homeostasis in mammals involves various sensors and controls operating in a negative-feedback loop. These include sensors of renal perfusion and tubular sodium delivery present within the kidney and effector hormones elaborated by endocrine organs. Key among them are renin, released by the juxtaglomerular cells lining afferent renal arterioles and neighboring macula densa cells of the distal tubule,9,10 and aldosterone produced by the adrenal glands (Figure 1). Renin cleaves four amino acids from circulating angiotensinogen, the angiotensin-peptide precursor produced by the liver, to form angiotensin I, a biologically inert decapeptide. Angiotensin-converting enzyme, which is bound to the plasma membrane of endothelial cells, cleaves two amino acids from angiotensin I to form angiotensin II. Angiotensin II has several important actions integral to maintaining circulatory homeostasis, including promoting the constriction of the arterioles within the renal and systemic circulations and the reabsorption of sodium in proximal segments of the nephron. It also stimulates the adrenal cortex to secrete aldosterone, which promotes the reabsorption of sodium (in exchange for potassium) in distal segments of the nephron and in the colon and the salivary and sweat glands. From a teleologic perspective, the evolution of the renin–angiotensin–aldosterone system was a delayed event necessitated by periods of salt deprivation or the loss of salt and water and the need to retain them.10

Figure 1. The Renin–Angiotensin–Aldosterone System. Angiotensinogen, the precursor of all angiotensin peptides, is synthesized by the liver. In the circulation it is cleaved by renin, which is secreted into the lumen of renal afferent arterioles by juxtaglomerular cells. Renin cleaves four amino acids from angiotensinogen, thereby forming angiotensin I. In turn, angiotensin I is cleaved by angiotensin-converting enzyme (ACE), an enzyme bound to the membrane of endothelial cells, to form angiotensin II. In the zona glomerulosa of the adrenal cortex, angiotensin II stimulates the production of aldosterone. Aldosterone production is also stimulated by potassium, corticotropin, catecholamines (e.g., norepinephrine), and endothelins.

Variations in renin secretion occur in response to variations in intake of sodium and water; renin secretion is inhibited when salt and water are taken in and activated when they are not.11 There can therefore be periodicity to the activation of this system throughout a given day, depending on the frequency of food intake, or over the course of many days, when periods of starvation alternate with the consumption of food and water. The reductions in renal perfusion that normally occur with the assumption of an upright posture and during ambulation also stimulate renin secretion.12

The renin–angiotensin–aldosterone system preserves circulatory homeostasis in response to a loss of salt and water, such as that which can occur with intense and prolonged sweating caused by high ambient temperatures, vomiting, or diarrheal illness. Plasma concentrations of the system's effector hormones rise quickly in response to a contraction of intravascular volume and a reduction in renal perfusion. Angiotensin II is the principal stimulator of aldosterone production when intravascular volume is reduced.1,13

Potassium is also a major physiologic stimulus to aldosterone production; aldosterone secretion is integral to potassium homeostasis because aldosterone has the ability to increase potassium excretion in urine, feces, sweat, and saliva.14,15 Aldosterone thereby serves to prevent hyperkalemia during periods of high potassium intake. For example, aldosterone secretion rises after the consumption of foods high in potassium content or after vigorous physical activity that causes the release of potassium from skeletal muscle. The importance of aldosterone in potassium homeostasis is most evident in patients with aldosterone insufficiency (Addison's disease), in whom hyperkalemia is common and can be reversed by treatment with a mineralocorticoid.16

Further evidence of the importance of potassium as a stimulus to aldosterone production comes from studies in genetically manipulated mice that do not express the angiotensin precursor angiotensinogen and therefore have little or no angiotensin II.17 In these animals, dietary sodium deprivation causes hyperkalemia, which, in turn, increases aldosterone secretion, thereby stimulating the reabsorption of salt and water and maintaining extracellular fluid volume. Restriction of both dietary sodium and potassium leads to hypotension and death in these animals.

In addition to their individual effects on salt and water homeostasis, angiotensin II and aldosterone have other endocrine actions relevant to the maintenance of circulatory homeostasis. They contribute to the coagulation of blood, in part through the increased production of plasminogen-activator inhibitor type 1 and the aggregation and activation of platelets at sites of bleeding18; they constrict systemic arterioles to preserve arterial pressure in the face of contraction of the intravascular volume13; and they stimulate thirst.10

Angiotensin II and aldosterone are also involved in regulating inflammatory and reparative processes that follow tissue injury.19,20 In this capacity, they stimulate cytokine production, inflammatory-cell adhesion, and chemotaxis; activate macrophages at sites of repair21; and stimulate the growth of fibroblasts and the synthesis of type I and III fibrillar collagens, which govern the formation of scar tissue.22

A substance produced by cells within a tissue can exert actions on the same or different cells; these effects are known, respectively, as autocrine and paracrine properties. Recent studies have demonstrated the presence of aldosterone synthase messenger RNA (mRNA) and its activity together with aldosterone production by endothelial and vascular smooth-muscle cells in the heart and blood vessels (Figure 2).24,25,26 Once considered the sole province of the zona glomerulosa of the adrenal glands because of the key enzymes involved in its steroidogenesis, the production of aldosterone by the heart is regulated by angiotensin II and by modifications in dietary sodium and potassium. The physiologic importance of locally produced aldosterone is not known, but early findings suggest that it may contribute to tissue repair after myocardial infarction.27

Figure 2. Extraadrenal Production of Aldosterone by Endothelial and Vascular Smooth-Muscle Cells in an Intramyocardial Coronary Artery. Modified from Slight et al.23 with the permission of the publisher.