Renin, aldosterone synthesis

Atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) are members of a family of so-called natriuretic peptides, synthesized predominantly in the cardiac atrium, ventricle, and vascular endothelial cells, respectively (G13, Y2). ANP is a 28-amino-acid polypeptide hormone released into the circulation in response to atrial stretch (L3). ANP acts (Fig. 8) on the kidney to increase sodium excretion and glomerular filtration rate (GFR), to antagonize renal vasoconstriction, and to inhibit renin secretion (Ml). In the cardiovascular system, ANP antagonizes vasoconstriction and shifts fluid from the intravascular to the interstitial compartment (G14). In the adrenal cortex, ANP is a powerful inhibitor of aldosterone synthesis (E6, N3). At the hypothalamic level, ANP inhibits vasopressin secretion (S3). It has been shown that some of the effects of ANP are mediated via a newly discovered hormone, called adreno-medullin, controlling fluid and electrolyte homeostasis (S8). The diuretic and blood pressure-lowering effect of ANP may be partially due to adrenomedullin (V5). 

The adrenocorticotrophic hormone ACTH (corticotropin) stimulates the adrenal cortex to secrete the glucocorticoids hydrocortisone (cortisol) and corticosterone, the mineralocorticoid aldosterone, and a number of weakly androgenic substances, as well as a small amount of testosterone. Aldosterone synthesis is also regulated by renin and angiotensin. 

The major regulators of aldosterone secretion are the renin-angiotensin system and extracellular potassium ions (K+). The former is sensitive to changes in intravascular volume and arterial pressure, while the latter is an aldosterone-regulated substance that feeds back to reduce aldosterone synthesis (simple negative feedback). Aldosterone secretion is also influenced (but not regulated) by ACTH and, directly and indirectly, by atrial natriuretic factor (ANF). 

Aldosterone is produced exclusively by the zona glomerulosa and is primarily controlled by the renin-angiotensin system (p. 1.5). The metabolic pathway for the synthesis of aldosterone has many of the same enzymes involved in cortisol biosynthesis. The glomerular z.one lacks the 17-hydroxylase enzyme and has the additional 18-hydroxylase and 18-hydroxysteroid dehydrogenase enzymes necessary for aldosterone synthesis. 

The kidney contains the major site of renin synthesis, the juxtaglomerular cells in the wall of the afferent arteriole. From these cells, renin is secreted not only into the circulation but also into the renal interstitium. Moreover, the enzyme is produced albeit in low amounts by proximal tubular cells. These cells also synthesize angiotensinogen and ACE. The RAS proteins interact in the renal interstitium and in the proximal tubular lumen to synthesize angiotensin II. In the proximal tubule, angiotensin II activates the sodium/hydrogen exchanger (NHE) that increases sodium reabsorption. Aldosterone elicits the same effect in the distal tubule by activating epithelial sodium channels (ENaC) and the sodium-potassium-ATPase. Thereby, it also induces water reabsotption and potassium secretion. 

The zona glomerulosa is responsible for the production of the mineralocorticoids aldosterone, deoxycorticosterone, and 18-hydroxy-deoxycorticosterone. Aldosterone promotes renal sodium retention and excretion of potassium. Its synthesis and release are regulated by renin in response to decreased vascular volume and renal perfusion. Adrenal aldosterone production is regulated by the renin-angiotensin-aldosterone system. 

I to angiotensin II, a potent vasoconstrictor and stimulator of aldosterone secretion. ACE inhibitors also block the degradation of bradykinin and stimulate the synthesis of other vasodilating substances including prostaglandin E2 and prostacyclin. The fact that ACE inhibitors lower BP in patients with normal plasma renin activity suggests that bradykinin and perhaps tissue production of ACE are important in hypertension. 

Fluid retention A fall in cardiac output decreases blood flow to the kidney, prompting the release of renin, with a resulting increase in the synthesis of angiotensin II and aldosterone (see p. 181). This results in increased peripheral resistance and retention of sodium and water. Blood volume increases, and more blood is returned to the heart. If the heart is unable to pump this extra volume, venous pressure increases and peripheral edema and pulmonary edema occur (Figure 16.4). These compensatory responses increase the work of the heart and, therefore, can contribute to the further decline in cardiac function. 

Clinical signs of chronic renal failure primarily include (1) edema due to reduced renal perfusion leading to stimulation of the renin-angiotensin system, which stimulates aldosterone secretion leading to retention of sodium and water, (2) hypocalcemia with compensatory parathyroid activity and osteodystrophy, and (3) reduced red blood cell counts due to decreased synthesis of erythropoietin as a result of damage to the juxtaglomerular cells. 

NOTE Aldosterone production requires the renin-angiotension system Renin is an enzyme secreted by the juxtaglomerular ceils of the kidney in response to decreased arterial blood pressure and blood flow. Renin stimulates conversion of the protein angiotensinogen to angiotensin I which then becomes angiotensin II. Angiotensin II stimulates the synthesis and release of aldosterone by the adrenal cortex. 

The mineralocorticoids have a main action on the distal tubules in the kidney to increase sodium absorption, with concomitant increased excretion of K and H. Aldosterone is the main endogenous mineralocorticoid. It is produced in the outermost layer of the adrenal cortex (the zona glomerulosa). An excessive secretion of mineralocorticoids (e.g. in Conn s syndrome) causes marked salt and water retention, with a resultant increase in the volume of extracellular fluid, alkalosis, hyperkalaemia and often hypertension. A decrease in secretion (e.g. Addison s disease) causes a disproportional loss of Na compared to fluid loss, so osmotic pressure of the extracellular fluid is reduced. This results in an increase in intracellular compared to extracellular fluid volume. The concomitant decrease in excretion of K results in hyperkalaemia with some decrease in bicarbonate. The control of synthesis and release of aldosterone is complex and involves both the renin-angiotensin system and the electrolyte composition of the blood. As with other... 

Angiotensin II is involved in the renin-angiotensin-aldosterone system, which regulates blood pressure, sodium and water homoeostasis by the kidneys, and cardiovascular function. Angiotensin II stimulates the synthesis and secretion of aldosterone and raises blood pressure via a direct vasoconstrictor effect. 

The K. is the site of synthesis of Erythropoietin (see) and Renin (see). Renin is synthesized in the juxtaglomerular cells it releases Angiotensin (see), which in turn stimulates the release of aldosterone by the adrenal cortex. 25-Hydroxycholecalciferol (produced in the liver from vitamin D3 or cholecalci-ferol) is converted by the kidney into 1,25-dihydroxy-cholecalciferol, which promotes calcium uptake by the intestine and calcium mobilization in bone. 

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