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The Renin-Angiotensin System
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Even more important to the control of sodium excretion than sympathetic input by itself is the renin-angiotensin system. We will soon see that the renin-angiotensin system and the sympathetic nervous system are interacting systems and cannot be viewed as separate controllers. What is traditionally described as the renin-angiotensin system is really a set of renin-angiotensin systems. There is both a systemic circulating renin-angiotensin system, and separate organ specific renin-angiotensin systems in many tissues, including, but not limited to, the heart, sex organs, brain, and the kidneys. In addition, the circulating renin-angiotensin system is intimately involved in controlling the steroid hormone aldosterone. The circulating renin-angiotensin system can appropriately be called the RAAS.
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Renin-angiotensin systems are peptide-signaling systems that regulate multiple processes in the kidney and elsewhere. They consist of a protein substrate (angiotensinogen), the enzyme renin that splits off a 10 amino acid peptide (angiotensin I) from angiotensinogen, several additional enzymes that split angiotensin I into smaller peptides, and finally receptors for the peptides that activate cellular actions upon binding. The most important of these smaller peptides is the 8 amino acid peptide angiotensin II (AII). It is formed from angiotensin I by the action of angiotensin converting enzyme (ACE). AII is a mediator of multiple effects in the kidneys and elsewhere.
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In the circulating RAAS, angiotensinogen is synthesized in the liver (Figure 7–3). Plasma angiotensinogen levels are normally high and do not limit the production of AII. Furthermore, ACE, which is expressed on the endothelial surfaces of the vascular system, particularly the pulmonary vessels, avidly converts most of the angiotensin I into AII. Therefore, the major determinant of circulating AII is the amount of renin available to form angiotensin I. As outlined in Chapter 1 and shown in Figure 7–4, renin is produced by the juxtaglomerular (jg) apparatus. The renin-secreting cells are located in the late afferent arteriole just before the glomerulus, and are referred to as juxtaglomerular granular cells (because renin can be visualized as secretory granules). The secretion of renin by the granular cells is under the control of 3 primary regulators described below.
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AII is a potent vasoconstrictor, acting on the vasculature of many peripheral tissues, the effect of which is to raise arterial pressure. It also vasoconstricts both cortical and medullary vessels in the kidney. This reduces total RBF and reduces GFR, thus decreasing the filtered load of sodium. A number of drugs for the treatment of hypertension either reduce the production of AII (ACE inhibitors) or block the peripheral receptors for AII (see later discussion).
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Stimulation of sodium tubular reabsorption—
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AII stimulates sodium reabsorption in both the proximal tubule and distal nephron. In the proximal tubule it stimulates the same transcellular transport pathway as does norepinephrine, namely the NHE3 sodium/hydrogen antiporter in the apical membrane and the Na-K-ATPase in the basolateral membrane. In the distal tubule and connecting tubule, it stimulates the activity of sodium/chloride symporters and sodium channels (ENaC) that reabsorb sodium.
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Angiotensin II is a hugely important agent to preserve blood volume and blood pressure. It directly stimulates sodium reabsorption, stimulates aldosterone secretion, and causes general vasoconstriction.
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Stimulation of the CNS: salt appetite, thirst, and sympathetic drive—
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AII stimulates behavioral actions in response to fluid loss that increase salt appetite and thirst. AII acts on the circumventricular organs in the brain that are described later in this chapter. These function as detectors of many substances in the blood and convey information to various areas of the brain. In situations of volume depletion and low blood pressure, when circulating levels of AII are high, a key effect, in addition to vascular and tubular actions is increased thirst and salt appetite. These pathways also increase sympathetic drive.
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Stimulation of aldosterone secretion—
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Aldosterone is a major stimulator of sodium reabsorption in the distal nephron, that is, regions of the tubule beyond the proximal tubule and loop of Henle. Aldosterone-stimulated sodium retention is an effector system that is vital in correcting prolonged reductions in body sodium, blood pressure, and volume. We focus here on the role of aldosterone in sodium reabsorption, but aldosterone has many other important actions, including stimulation of potassium excretion and acid excretion (see Chapters 8 and 9).
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The most important physiological factor controlling secretion of aldosterone is the circulating level of AII, which stimulates the adrenal cortex to produce aldosterone. This targets the distal nephron to increase sodium reabsorption and thus increase total body sodium and blood volume to produce a long-term correction to total body sodium content and mean blood pressure.
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The main cellular targets of aldosterone are the principal cells in the cortical connecting tubule and principal cells in the cortical collecting duct. An action on this late portion of the nephron is what one would expect for fine-tuning the output of sodium, because more than 90% of the filtered sodium has already been reabsorbed by the time the filtrate reaches the collecting-duct system.
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As a molecule, aldosterone has enough lipid character to freely cross principal cell membranes, after which it combines with mineralocorticoid receptors in the cytoplasm. After being transported to the nucleus, the receptor acts as a transcription factor that promotes gene expression of specific proteins. The effect of these proteins is to increase the activity or number of luminal membrane sodium channels (ENaCs) and basolateral membrane Na-K-ATPase pumps. Thus, the 2 major elements in transcellular sodium reabsorption are stimulated (Figure 7–5).
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The percentage of sodium reabsorption dependent on the influence of aldosterone is approximately 2% of the filtered load. Thus, all other factors remaining constant, in the complete absence of aldosterone, a person would excrete 2% of the filtered sodium, whereas in the presence of high plasma concentrations of aldosterone, virtually no sodium would be excreted. Two percentage of the filtered sodium may seem trivial but is actually a significant amount because so much sodium is filtered:
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Equation 7-4
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Thus, aldosterone controls the reabsorption of 0.02 × 25,200 mmol/day = 504 mmol/day. In terms of sodium chloride, the form in which most sodium is ingested, this amounts to the control of almost 30 g NaCl/day, an amount considerably more than the average person consumes. Therefore, by control of the plasma concentration of aldosterone between minimal and maximal, the excretion of sodium can be finely adjusted to the intake so that total body sodium remains constant.
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Aldosterone also stimulates sodium transport by other epithelia in the body, namely, sweat and salivary ducts and the intestine. The net effect is the same as that exerted on the kidney: movement of sodium from lumen to blood. Thus, aldosterone is an all-purpose stimulator of sodium retention.
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AII produced by the circulating RAAS system is the main stimulator of aldosterone secretion. Since levels of AII are controlled by renin, this emphasizes the importance of renin in the control of sodium reabsorption. Both renin and aldosterone have relatively short plasma half-lives (∼15 minutes), whereas the half-life of AII is very short (<1 minute). Therefore, prolonged action of aldosterone requires the continuous stimulation of renin secretion.
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Although we have emphasized the importance of AII as a stimulator of aldosterone secretion, there are other aldosterone controllers that play significant roles also. A complication in the operation of the RAAS is the role of AII and aldosterone in potassium and acid excretion. An elevated plasma potassium concentration is a stimulator of aldosterone secretion, and depletion of potassium is an inhibitor and may in some cases counteract the stimulating effect of AII. We will address this topic in Chapter 8. The atrial natriuretic factors (discussed later) also inhibit aldosterone secretion.
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From all of the preceding discussion it should be clear that AII is a hugely important agent to preserve blood volume and blood pressure. It does so by retaining sodium, both through its own actions and via aldosterone, and by causing general vasoconstriction. The major actions of AII that lead to sodium retention and increased blood pressure are shown in Table 7–1. We will describe its influence on potassium excretion in Chapter 8.
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Control of the circulating RAAS—
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The activity of the circulating RAAS is governed by the amount of renin secreted by the granular cells of the jg apparatus. There are 3 major controllers of renin secretion. The first controller is sympathetic input. Norepinephrine released from postganglionic sympathetic neurons acts on β1-adrenergic receptors in the granular cells. This activates a c-AMP-mediated pathway that causes the release of renin. The granular cells are quite sensitive to norepinephrine and respond to low levels of sympathetic activity that may have minimal direct effect on the renal vasculature or sodium transport. As described earlier, sympathetic drive is highly influenced by feedback detected by vascular pressures. Low pressures lead to increased sympathetic drive to the granular cells and increased release of renin.
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The second controller of renin secretion is pressure in the afferent arteriole. The granular cells not only respond to vascular pressures indirectly via adrenergic stimulation, they respond directly to changes in afferent arteriolar pressure. When pressure in the afferent arteriole decreases, renin production increases. Except in cases of major renal arterial blockage, pressure in the arteriolar lumen at the granular cells is close to systemic arterial pressure and changes in parallel with it. Because the granular cells respond to vascular pressure, they are acting as baroreceptors. In fact, the granular cells are the intrarenal baroreceptors mentioned previously. Even though they are not neurons and do not send afferent feedback, they are baroreceptors nevertheless. Consider what happens when arterial pressure drops. The intrarenal baroreceptors (the granular cells) sense the drop in pressure and increase their secretion of renin. Simultaneously, the drop in pressure is also sensed by the arterial baroreceptors in the carotid arteries and aorta. The fall in their afferent signaling allows the vasomotor center to increase sympathetic drive to the granular cells, resulting in a huge combined stimulation of renin secretion.
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The third controller of renin release originates from another component of the jg apparatus; namely the macula densa. The operation of the macula densa is somewhat complicated, but serves as a fascinating example of negative feedback in biological systems.
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Functions of the Macula Densa
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The macula densa is a detection system and initiator of feedback that helps regulate (1) renin secretion and (2) GFR. Regulation of GFR by the macula densa is called tubuloglomerular feedback (TG feedback), meaning from the tubule to the glomerulus. TG feedback is a component of the autoregulation of GFR described in Chapter 2. How do these 2 feedback systems work? The macula densa is located at the end of the loop of Henle where the tubule passes between the afferent and efferent arterioles of Bowman's capsule. It is able to sense (1) flow and (2) salt content in the tubular lumen that are the net result of filtration and reabsorption in tubular elements preceding it, that is, it senses “everything done so far.” Flow is sensed by cilia that project into the tubular lumen from macula densa cells. Bending of the cilia initiates intracellular signaling that leads to release of paracrine mediators. Tubular sodium chloride is sensed by uptake via Na-K-2Cl multiporters whose action changes ionic concentrations within the macula densa cells and also causes release of paracrine mediators. When tubular flow and sodium content are high it is as if “the body has too much sodium” and “GFR is too high.” The mediators released by the macula densa reduce the secretion of renin (thereby allowing more sodium excretion) and decrease GFR (restoring GFR to an appropriate level). The immediate mediator is ATP, which is converted extracellularly to adenosine. One or both bind to purinergic receptors on the nearby granular cells. This has the effect of increasing intracellular calcium and reducing the release of renin.4 In turn, the reduction in renin secretion reduces the levels of AII and allows the kidneys to excrete more of the filtered sodium. Simultaneously, the adenosine binds to purinergic receptors on afferent arteriole smooth muscle. The subsequent rise in calcium in these cells stimulates contraction, thus reducing pressure and flow through the glomerular capillaries and reducing GFR.
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The macula densa dampens changes in renin secretion and GFR caused by other controllers.
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What happens in the opposite case, that is, when there is low flow and low salt content flowing past the macula densa? Now “the body has too little sodium” and “GFR is too low.” This initiates the release of different mediators, specifically prostaglandins (eg, PGE2) and nitric oxide (NO). In the granular cells the prostaglandins stimulate or prolong the lifetime of c-AMP, thereby stimulating the release of renin. The now-activated RAAS reduces sodium excretion. In the afferent arteriole NO is a dilator of smooth muscle. The effect is to raise flow and pressure in the glomerular capillaries, and restore GFR to an appropriate level. The operation of the macula densa in feedback control of the RAAS and GFR autoregulation is shown in Figure 7–6.
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The TG feedback mechanism helps autoregulate GFR in individual nephrons, keeping filtration within an acceptable range while allowing other controllers to modify how much of the filtered sodium is reabsorbed. TG feedback doesn't initiate overall changes in GFR or prevent changes; rather, it dampens changes originating from other signaling systems, for example, sympathetic control, so that GFR doesn't vary “too much.” Keep in mind that changes in GFR affect not only sodium, but every other filtered substance, and the kidneys have to maintain appropriate filtration in order to avoid deleterious effects on the excretion of those other substances.
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Finally, descriptions of the RAAS quite naturally focus on its activation and subsequent stimulation of sodium reabsorption. This is because retention of sodium is crucial during hypovolemic emergencies and in unusual circumstances when dietary sodium is not plentiful. However, on typical Western diets the salt content of meals is often in excess, and it is imperative to let the kidneys excrete salt loads promptly. The main way this is accomplished is by decreasing the activity of the RAAS. Figure 7–7 summarizes control of renin secretion.
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Modulation of Sodium excretion: Dopamine
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The major regulators described in the preceding sections, that is, sympathetic input, AII and aldosterone all serve to increase sodium reabsorption. Another major regulator is dopamine, but its action is different—namely it inhibits sodium reabsorption. Dopamine is generally known as a neurotransmitter in the central nervous system that participates in multiple functions including the control of body movement. The dopamine that acts in the kidney is not released from neurons; rather it is synthesized in proximal tubule cells from the precursor l-DOPA (the same substance employed in the treatment of Parkinsonism). l-DOPA is taken up from the renal circulation and glomerular filtrate and converted to dopamine in the proximal tubule epithelium, and then released to act in a paracrine manner on nearby cells. Although the signaling path is not clear, it is known that increases in sodium intake lead to increased production of intrarenal dopamine. Dopamine has 2 actions, both of which reduce sodium reabsorption. First, it causes retraction of NHE antiporters and Na-K-ATPase pumps into intracellular vesicles, thereby reducing transcellular sodium reabsorption. Second, it reduces the expression of AII receptors, thereby decreasing the ability of AII to stimulate sodium reabsorption. Therefore dopamine, in combination with sympathetic input and the RAAS, comprises a true push-pull system that exerts bidirectional control over sodium reabsorption.
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Other Regulators and Influences on Sodium Excretion
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Changes in GFR, sympathetic input, the RAAS and dopamine are the most important means of regulating sodium excretion. As should be clear from the previous discussion, these processes influence each other, together yielding a final rate of sodium excretion that meets the goals outlined in the beginning of this chapter. There are still many other signals and processes that contribute to regulation, some of which are outlined below.
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We previously described the role of ADH in regulating the reabsorption of water in the collecting duct system and will address this topic again later in the chapter. ADH also plays a direct role in regulating sodium excretion. When ADH binds to V2 receptors in tubular cells, it increases the production of c-AMP. This results in increased activity of the NKCC multiporter in the thick ascending limb and increased sodium channel (ENaC) presence in principal cells of the distal nephron, thereby increasing the uptake of sodium that, in both regions, is actively transported into the interstitium by the Na-K-ATPase. Interestingly, in the distal nephron the mechanism proceeds, not by moving ENaCs into the membrane, but rather by decreasing their removal and degradation. As mentioned in Chapter 4, transport proteins have a finite lifetime in membranes before being degraded. A process that slows degradation of a transport protein has the same effect as increasing the expression and insertion of the protein.
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GLOMERULOTUBULAR BALANCE
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Glomerulotubular balance (not to be confused with TG feedback described previously) refers to the phenomenon whereby sodium reabsorption in the proximal tubule varies in parallel with the filtered load, such that approximately two thirds of the filtered sodium is reabsorbed even when GFR varies. As an example, consider what happens when GFR rises 20%. The filtered load rises 20%, but the absolute amount of sodium reabsorbed also rises 20%, and the fractional reabsorption remains at two thirds. Note that although two thirds of the larger filtered load is reabsorbed, the remaining one third of the larger filtered load is not reabsorbed, and the increased GFR still increases the absolute amount of sodium passed on to elements beyond the proximal tubule. The mechanism by which reabsorption varies with filtered load appears to be via mechanotransduction by the microvilli on the apical surface of the proximal tubule cells, similar in principle to mechanotransduction by primary cilia in the macula densa. As flow changes, the amount of bending of the microvilli changes, and this is converted by cellular mechanisms into changes in transport. Be aware that two thirds is only a rough approximation. The various controllers of sodium excretion operating in the proximal tubule are still functioning. In other words, sometimes exactly two thirds of the filtered load is reabsorbed. At other times, it might be somewhat more or somewhat less.
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PRESSURE NATRIURESIS AND DIURESIS
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Because the kidneys are responsive to arterial pressure, there are situations in which elevated blood pressure can lead directly to increased excretion of sodium, particularly if the body contains excess fluid. This phenomenon is called pressure natriuresis, and because natriuresis is usually accompanied by water (see later discussion), it is often called pressure diuresis. This is an intrarenal phenomenon, not requiring external signaling. However, external signals normally override pressure natriuresis, as occurs, for example, in aerobic exercise when arterial pressure is somewhat increased, but sodium excretion is decreased. In addition, a common cause of hypertension is renal pathology that inappropriately activates the intrarenal RAS. In these cases the elevated arterial pressure fails to increase sodium excretion.
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Several tissues in the body synthesize members of a hormone family called natriuretic peptides, so named because they promote excretion of sodium in the urine. Key among these are atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP; named as such because it was first discovered in the brain). The main source of both natriuretic peptides is the heart. The natriuretic peptides have both vascular and tubular actions. They relax the afferent arteriole, thereby promoting increased filtration, and act at several sites in the tubule. They inhibit release of renin, inhibit the actions of AII that normally promote reabsorption of sodium, and act in the medullary collecting duct to inhibit sodium absorption. The major stimulus for increased secretion of the natriuretic peptides is distention of the atria, which occurs during plasma volume expansion. This is probably the stimulus for the increased natriuretic peptides that occurs in persons on a high-salt diet. Although most experts assume that these peptides play some physiological role in the regulation of sodium excretion in this and other situations in which plasma volume is expanded, it is not currently possible to quantitate precisely their contribution, although it is surely less than aldosterone. These peptides are greatly elevated in patients with heart failure and can serve as diagnostic indicators.
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Summary of the Control of Sodium Excretion
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Sodium excretion is controlled by an array of interacting control systems relating to the CV system, the most important of which are sympathetic outflow, the RAAS system and dopamine (Figure 7–8). Some controllers increase sodium excretion; others decrease it. Intrarenal signaling is bidirectional. The main goal of control is to preserve a total mass of sodium in the extracellular fluid that maintains appropriate osmotic content for the CV system. The important detection systems include baroreceptors in various locations and cells in the CNS that detect sodium concentration. Neural baroreceptors respond to pressures in the arterial system, and in the heart and pulmonary circuit, thereby providing information about volume, whereas intrarenal baroreceptors give additional information about arterial pressure. Control systems alter vascular resistances and the activity of renal transport proteins. Although changes in GFR contribute to the regulation of sodium excretion, changes in rates of sodium reabsorption are more important. Sodium deficits elicit strong responses to conserve sodium, mostly by increasing tubular reabsorptive processes in all nephron segments. Excess sodium is excreted primarily by decreasing tubular reabsorption. Under all circumstances, even with considerable excess dietary sodium, the vast majority of filtered sodium (over 98%) is reabsorbed, but because so much sodium is filtered, even small adjustments in reabsorption result in large cumulative changes in total body sodium.
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