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BIOSYNTHESIS OF ANGIOTENSIN
The pathway for the formation and metabolism of angiotensin (ANG II) is summarized in Figure 17–1. The principal steps include enzymatic cleavage of angiotensin I (ANG I) from angiotensinogen by renin, conversion of ANG I to ANG II by converting enzyme, and degradation of ANG II by several peptidases.
Renin is an aspartyl protease enzyme that specifically catalyzes the hydrolytic release of the decapeptide ANG I from angiotensinogen. It is synthesized as a prepromolecule that is processed to prorenin, which has poorly understood actions , and then to active renin, a glycoprotein consisting of 340 amino acids.
Renin in the circulation originates in the kidneys. Enzymes with renin-like activity are present in several extrarenal tissues, including blood vessels, uterus, salivary glands, and adrenal cortex, but no physiologic role for these enzymes has been established. Within the kidney, renin is synthesized and stored in the juxta-glomerular apparatus of the nephron. Specialized granular cells called juxtaglomerular cells are the site of synthesis, storage, and release of renin. The macula densa is a specialized segment of the nephron that is closely associated with the vascular components of the juxtaglomerular apparatus. The vascular and tubular compo-nents of the juxtaglomerular apparatus, including the juxtaglom-erular cells, are innervated by noradrenergic neurons.
The rate at which renin is released by the kidney is the primary determinant of activity of the renin-angiotensin system.
Active renin is released by exocytosis immediately upon stimulation of the juxtaglomerular apparatus. Prorenin is released constitutively, usually at a rate higher than that of active renin, thus accounting for the fact that prorenin can constitute 80–90% of the total renin in the circulation. The significance of circulating prorenin is dis-cussed at the end of this section. Active renin release is controlled by a variety of factors, including a renal vascular receptor, the macula densa, the sympathetic nervous system, and ANG II.
Renin release is controlled in part by the macula densa, a structure that has a close anatomic association with the afferent arteriole. The initial step involves the detection of some function of NaCl concentration in, or delivery to, the distal tubule, possibly by the Na+/K+/2Cl– cotransporter. The macula densa then signals changes in renin release by the juxtaglomerular cells such that there is an inverse relationship between NaCl delivery or concentration and renin release. Potential candidates for signal transmission include prostaglandin E2 (PGE2) and nitric oxide, which stimulate renin release, and adenosine, which inhibits it.
The renal baroreceptor mediates an inverse relationship between renal artery pressure and renin release. The mechanism is not completely understood but it appears that the juxtaglomerular cells are sensitive to stretch and that increased stretch results in decreased renin release. The decrease may result from influx of calcium which, somewhat paradoxically, inhibits renin release. The paracrine factors PGE2, nitric oxide, and adenosine have also been implicated in the baroreceptor control of renin release.
Norepinephrine released from renal sympathetic nerves stimu-lates renin release indirectly by α-adrenergic activation of the renal baroreceptor and macula densa mechanisms, and directly by an action on the juxtaglomerular cells. In humans, the direct effect is mediated by β1 adrenoceptors. Through this mecha-nism, reflex activation of the sympathetic nervous system by hypotension or hypovolemia leads to activation of the renin-angiotensin system.
Angiotensin II inhibits renin release. The inhibition results from increased blood pressure acting by way of the renal baroreceptor and macula densa mechanisms, and from a direct action of the peptide on the juxtaglomerular cells. The direct inhibition is mediated by increased intracellular Ca2+ concentration and forms the basis of a short-loop negative feedback mechanism controlling renin release. Interruption of this feedback with drugs that inhibit the renin-angiotensin system results in stimulation of renin release.
The release of renin by the juxtaglomerular cells is controlled by interplay among three intracellular messengers: cAMP, cyclic guanosine monophosphate (cGMP), and free cytosolic Ca2+ con-centration (Figure 17–2). cAMP plays a major role; maneuvers that increase cAMP levels, including activation of adenylyl cyclase, inhibition of cAMP phosphodiesterases, and administration of cAMP analogs, increase renin release. Increases in Ca2+ can result from increased entry of extracellular Ca2+ or mobilization of Ca2+ from intracellular stores, while increases in cGMP levels can result from activation of soluble or particulate guanylyl cyclase. Ca2+ and cGMP appear to alter renin release indirectly, primarily by chang-ing cAMP levels.
The release of renin is altered by a wide variety of pharmacologic agents. Renin release is stimulated by vasodilators (hydralazine, minoxidil, nitroprusside), β-adrenoceptor agonists, α-adrenoceptor antagonists, phosphodiesterase inhibitors (eg, theophylline, milri-none, rolipram), and most diuretics and anesthetics. This stimula-tion can be accounted for by the control mechanisms just described. Drugs that inhibit renin release are discussed below.
Many of the peptides reviewed also alter renin release. Release is stimulated by adrenomedullin, bradykinin, and calcitonin gene-related peptide, and inhibited by atrial natriuretic peptide, endothelin, substance P, and vasopressin.
Angiotensinogen is the circulating protein substrate from which renin cleaves ANG I. It is synthesized in the liver. Human angio-tensinogen is a glycoprotein with a molecular weight of approxi-mately 57,000. The 14 amino acids at the amino terminal of the molecule are shown in Figure 17–1. In humans, the concentra-tion of angiotensinogen in the circulation is less than the Km of the renin-angiotensinogen reaction and is therefore an impor-tant determinant of the rate of formation of angiotensin.The production of angiotensinogen is increased by corticosteroids, estrogens, thyroid hormones, and ANG II. It is also elevated during pregnancy and in women taking estrogen-containing oral contracep-tives. The increased plasma angiotensinogen concentration is thought to contribute to the hypertension that may occur in these situations.
Although ANG I contains the peptide sequences necessary for all of the actions of the renin-angiotensin system, it has little or no biologic activity. Instead, it must be converted to ANG II by con-verting enzyme (Figure 17–1). ANG I may also be acted on by plasma or tissue aminopeptidases to form [des-Asp1]angiotensin I; this in turn is converted to [des-Asp1]angiotensin II (commonly known as angiotensin III) by converting enzyme.
Converting enzyme is a dipeptidyl carboxypeptidase with two active sites that catalyzes the cleavage of dipeptides from the carboxyl terminal of certain peptides. Its most important sub-strates are ANG I, which it converts to ANG II, and bradykinin, which it inactivates (see Kinins, below). It also cleaves enkepha-lins and substance P, but the physiologic significance of these effects has not been established. The action of converting enzyme is prevented by a penultimate prolyl residue in the sub-strate, and ANG II is therefore not hydrolyzed by converting enzyme. Converting enzyme is distributed widely in the body. In most tissues, converting enzyme is located on the luminal sur-face of vascular endothelial cells and is thus in close contact with the circulation.
A homolog of converting enzyme known as ACE2 was recently found to be highly expressed in vascular endothelial cells of the kidneys, heart, and testes. Unlike converting enzyme, ACE2 has only one active site and functions as a carboxypeptidase rather than a dipeptidyl carboxypeptidase. It removes a single amino acid from the C-terminal of ANG I forming ANG 1-9 (Figure 17–3), which is inac-tive but is converted to ANG 1-7 by ACE. ACE2 also converts ANG II to ANG 1-7. ANG 1-7 has vasodilator activity, apparently medi-ated by the orphan heterotrimeric guanine nucleotide-binding pro-tein-coupled receptor (Mas receptor).
This vasodilation may serve to counteract the vasoconstrictor activity of ANG II. ACE2 also differs from ACE in that it does not hydrolyze bradykinin and is not inhib-ited by converting enzyme inhibitors . Thus, the enzyme more closely resembles an angiotensinase than a converting enzyme.
Angiotensin II, which has a plasma half-life of 15–60 seconds, is removed rapidly from the circulation by a variety of peptidases col-lectively referred to as angiotensinase. It is metabolized during passage through most vascular beds (a notable exception being the lung). Most metabolites of ANG II are biologically inactive, but the initial product of aminopeptidase action—[des-Asp1]angiotensin II—retains considerable biologic activity.
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