Aldosterone’s primary function is to act on the late distal tubule and collecting duct of nephrons in the kidney, directly impacting sodium absorption and potassium excretion. It also indirectly affects the excretion of hydrogen ions by changing the amount of potassium in the lumen of the nephron, causing downstream consequences on alpha-intercalated cells. Lastly, it affects blood pressure through regulating the amount of sodium (and the chloride that diffuses with sodium across the membranes) by increasing or decreasing the total amount of volume in the extracellular fluid (ECF). However, this is not to be confused with the effect of anti-diuretic hormone (ADH). ADH is often released simultaneously with aldosterone. This allows for blood pressure control by causing the release and fusion of aquaporin channels into the membrane of the principal cells. Water will then be reabsorbed into the ECF. Together these two hormones can cause an increase in the amount of water taken up through the nephron, therefore increasing blood pressure.
Aldosterone is created from cholesterol within the zona glomerulosa of the adrenal glands. Cholesterol interacts with the enzymes 3-beta-hydroxysteroid dehydrogenase, 21-alpha-hydroxylase, 11-beta-hydroxylase, and aldosterone synthase to produce 11-beta, 21-dihydroxy-3, 20-dioxopregn-4-en-18-al (aldosterone). These enzymes are also interconnected with the production of other steroid hormones made in the adrenal glands via cholesterol, including glucocorticoids (corticosterone and cortisol) and androgen hormones (estrone, estradiol, and dihydrotestosterone).
Congenital adrenal hyperplasia (CAH) can take many forms, depending on which enzymes are deficient. The three main enzyme deficiencies that affect aldosterone are deficiencies in 21-hydroxylase, 11-beta-hydroxylase, and aldosterone synthase. Deficiency in any of these enzymes will halt aldosterone production. This leads to a buildup of intermediary products, therefore, causing cholesterol to be funneled down the androgen hormone production pathway. Depending on the severity of the enzyme deficiency, this can result in hyponatremia, hyperkalemia (due to the inability to exchange sodium for potassium in the nephron), and hypovolemia (low sodium causes a decrease in the ECF). In aldosterone synthase deficiency, many effects are mitigated by the fact that corticosterone is still made which acts similarly to aldosterone. The shunting of cholesterol toward the 17-alpha-hydroxylase pathway (androgen hormone production pathway) can result in virilization and ambiguous genitalia in females.
The organs involved in the renin-angiotensin system are the kidneys and the lungs (where angiotensin 1 gets converted to angiotensin 2).
Aldosterone affects the final part of electrolyte and water absorption within the nephron before excretion in the urine. As a result, aldosterone only affects about 3% of the total water absorption and is utilized in the fine-tuning of absorption. Steroid hormones accomplish this by diffusing into principle cells within the late distal tubule and collecting duct, where it acts on the nucleus of the cell to increase mRNA synthesis. These mRNAs are then used to increase the expression of sodium channels, sodium-potassium ATPase, and enzymes of the citric acid cycle.
Within the principal cells of the late distal tubule and collecting ducts, aldosterone increases the expression of sodium channels and sodium-potassium ATPase in the cell membrane. The sodium channels are on the luminal side of the principal cells and allow sodium to passively diffuse into the principle cells due to the transepithelial potential difference of -50 mV. This gradient is maintained by the sodium-potassium ATPase on the basolateral side, which uses ATP to actively transport sodium into the blood and potassium into the cell. There are also potassium channels on the luminal side of the cell that allow passive diffusion out of the cell into the lumen of the kidney whenever a sodium ion enters the cell. The net effect of this process is sodium absorption from the lumen, which allows for water absorption, assuming ADH is present to make the cells permeable to water. This directly results in an increase in osmolality within the blood, causing water to flow down its concentration gradient.
The most common test to assess disturbances of the aldosterone pathway is the aldosterone: renin ratio. This determines whether there is an isolated aldosterone problem or there is a disturbance within renin angiotensin system. If an aldosterone problem is suspected, and the results show no elevation in either aldosterone or renin, then congenital adrenal hyperplasia is suspected. If both aldosterone and renin are increased, and their ratio is less than 10, then the differential includes renovascular hypertension. If the renin value is normal, the aldosterone level is elevated, and the ratio is greater than 30, the differential includes Conns syndrome. This can be confirmed with a salt suppression test, an MRI of the adrenal glands, and adrenal vein sampling.
The release of aldosterone from the adrenal glands is regulated via the renin-angiotensin II-aldosterone system. This system is initially activated via a decrease in the mean arterial blood pressure to increase the blood pressure. The decrease in blood pressure is initially sensed within the afferent arterioles of the kidney. Prorenin is then released by mechanoreceptors and is converted to renin by the juxtaglomerular cells (JG cells). The JG cells can also release renin after sympathetic stimulation of their beta one receptor. Renin is the enzyme that converts angiotensinogen to angiotensin I. Angiotensin I then is converted to angiotensin II in the lungs and kidneys by angiotensin converting enzymes (ACE). Angiotensin II is an octapeptide that is activated by type-1, G protein-coupled angiotensin II receptors. These receptors have different functions depending on the types of cells that contain the receptor. However, it has five primary functions that include: increasing aldosterone, increasing sodium-hydrogen exchange within the proximal renal tubule, increasing thirst drive within the hypothalamus, increasing antidiuretic hormone, and acting on G protein-coupled receptors that activate IP3/Ca2+ second messenger systems within arterioles to cause vasoconstriction. Aldosterone then undergoes its actions within the kidney.
Aldosterone is clinically significant for two reasons. An increase or decrease in aldosterone can cause disease and medications affecting its function alter blood pressure. Changes in concentration of aldosterone, either too much (Conn syndrome and renovascular hypertension) or too little (certain types of Addison's disease and congenital adrenal hyperplasia), can result in disastrous effects on the body.
Hyperaldosteronism is caused by either a primary tumor within the adrenal gland (Conn syndrome) or via renovascular hypertension. A primary tumor within the adrenal gland causes an uncontrolled production and release of aldosterone. Renovascular hypertension increases aldosterone through two primary mechanisms: fibromuscular dysplasia (usually in young females) and atherosclerosis (usually in older individuals). Both decreased profusion to the afferent arterioles of the kidney causes the renin-angiotensin system to be activated. This causes uncontrolled hypertension and hypokalemia.
Addison’s disease is characterized by a hypo-functioning adrenal gland. However, depending on the cause of Addison’s disease, the regulation of aldosterone may be unaffected. Aldosterone is only affected by Addison’s disease when the adrenal gland undergoes destruction, for example, in autoimmune mediated destruction. Aldosterone is controlled by the renin-angiotensin system, while the rest of the adrenal glands hormone production is controlled by adrenocorticotropic hormone (ACTH). Therefore, in cases of Addison’s disease caused by pituitary dysfunction, adrenal insufficiency will exist, but with appropriate aldosterone levels. This is due to the fact the renin-angiotensin system remains intact.
Contraction alkalosis is a side effect of increased absorption of water via aldosterone and ADH pathways during a volume depleted state. The body senses a low mean arterial blood pressure when the ECF is low. Therefore the renin-angiotensin system is activated. This causes an increase in water absorption as well as activation of aldosterone. Aldosterone causes sodium to be absorbed and potassium to be excreted into the lumen by principal cells. In alpha intercalated cells, located in the late distal tubule and collecting duct, hydrogen ions and potassium ions are exchanged. Hydrogen is excreted into the lumen, and the potassium is absorbed. This mechanism prevents the body from losing too much potassium, which causes a relative depletion of hydrogen ions in the blood causing an alkalotic state.
Beta agonists/antagonists can cause the increase or decrease of renin by the JG cells, which translates to an increase or decrease in aldosterone.
Angiotensin converting enzyme inhibitors, a common class of hypertensive medications, blocks ACE from producing angiotensin II which results in a decrease aldosterone.
Angiotensin II receptor blockers (ARBs) block angiotensin II receptors which result in a decrease in aldosterone. This class of medications is used to control blood pressure when a patient has an intolerance to ACE-I.
Spironolactone is an aldosterone receptor blocker, which prevents aldosterone from acting on the receptors within the principal cells of the kidney.
Amiloride and triamterene are medications that block the sodium channels on the luminal side of the principal cells within the kidney. This prevents aldosterone from exerting its full effect on the kidney.
Generally speaking, all of these medications block the function of aldosterone, which prevents sodium absorption and potassium excretion. Therefore, possible side effects to all of these medications are hyponatremia, hyperkalemia, and hypovolemia.