MECHANISM OF URINE FORMING. ROLE OF KIDNEYS IN SUPPORTING OF HOMEOSTASIS

 

In anatomy, urinary system, the kidneys filter wastes (such as urea) from the blood and excrete them, along with water, as urine. The medical field that studies the kidneys and diseases of the kidney is called nephrology (nephro- meaning kidney is from the Ancient Greek word nephros; the adjective renal meaning related to the kidney is from Latin rēnēs, meaning kidneys).

In humans, the kidneys are located in the posterior part of the abdomen. There is one on each side of the spine; the right kidney sits just below the liver, the left below the diaphragm and adjacent to the spleen. Above each kidney is an adrenal gland (also called the suprarenal gland). The asymmetry within the abdominal cavity caused by the liver results in the right kidney being slightly lower than the left one while the left kidney is located slightly more medial.

The kidneys are retroperitoneal, which means they lie behind the peritoneum, the lining of the abdominal cavity. They are approximately at the vertebral level T12 to L3. The upper parts of the kidneys are partially protected by the eleventh and twelfth ribs, and each whole kidney is surrounded by two layers of fat (the perirenal and pararenal fat) which help to cushion it. Congenital absence of one or both kidneys, known as unilateral or bilateral renal agenesis can occur.

 Organization

Above each human kidney is one of the two adrenal glands.

In a normal human adult, each kidney is about 10 cm long, 5.5 cm in width and about 3 cm thick, weighing 150 grams.[1] Together, kidneys weigh about 0.5% of a person's total body weight. The kidneys are "bean-shaped" organs, and have a concave side facing inwards (medially). On this medial aspect of each kidney is an opening, called the hilum, which admits the renal artery, the renal vein, nerves, and the ureter.

The outer portion of the kidney is called the renal cortex, which sits directly beneath the kidney's loose connective tissue/fibrous capsule. Deep to the cortex lies the renal medulla, which is divided into 10-20 renal pyramids in humans. Each pyramid together with the associated overlying cortex forms a renal lobe. The tip of each pyramid (called a papilla) empties into a calyx, and the calices empty into the renal pelvis. The pelvis transmits urine to the urinary bladder via the ureter.

Blood supply

Each kidney receives its blood supply from the renal artery, two of which branch from the abdominal aorta. Upon entering the hilum of the kidney, the renal artery divides into smaller interlobar arteries situated between the renal papillae. At the outer medulla, the interlobar arteries branch into arcuate arteries, which course along the border between the renal medulla and cortex, giving off still smaller branches, the cortical radial arteries (sometimes called interlobular arteries). Branching off these cortical arteries are the afferent arterioles supplying the glomerular capillaries, which drain into efferent arterioles. Efferent arterioles divide into peritubular capillaries that provide an extensive blood supply to the cortex. Blood from these capillaries collects in renal venules and leaves the kidney via the renal vein. Efferent arterioles of glomeruli closest to the medulla (those that belong to juxtamedullary nephrons) send branches into the medulla, forming the vasa recta. Blood supply is intimately linked to blood pressure.

The basic functional unit of the kidney is the nephron, of which there are more than a million within the cortex and medulla of each normal adult human kidney. Nephrons regulate water and solute within the cortex and medulla of each normal adult human kidney. Nephrons regulate water and soluble matter (especially electrolytes) in the body by first filtering the blood under pressure, and then reabsorbing some necessary fluid and molecules back into the blood while secreting other, unneeded molecules. Reabsorption and secretion are accomplished with both cotransport and countertransport mechanisms established in the nephrons and associated collecting ducts.

 Collecting duct system

The fluid flows from the nephron into the collecting duct system. This segment of the nephron is crucial to the process of water conservation by the organism. In the presence of antidiuretic hormone (ADH; also called vasopressin), these ducts become permeable to water and facilitate its reabsorption, thus concentrating the urine and reducing its volume. Conversely, when the organism must eliminate excess water, such as after excess fluid drinking, the production of ADH is decreased and the collecting tubule becomes less permeable to water, rendering urine dilute and abundant. Failure of the organism to decrease ADH production appropriately, a condition known as syndrome of inappropriate ADH (SIADH), may lead to water retention and dangerous dilution of body fluids, which in turn may cause severe neurological damage. Failure to produce ADH (or inability of the collecting ducts to respond to it) may cause excessive urination, called diabetes insipidus (DI).

A second major function of the collecting duct system is the maintenance of acid-base homeostasis.

After being processed along the collecting tubules and ducts, the fluid, now called urine, is drained into the bladder via the ureter, to be finally excluded from the organism.

 Excretion of waste products

The kidneys excrete a variety of waste products produced by metabolism, including the nitrogenous wastes: urea (from protein catabolism) and uric acid (from nucleic acid metabolism).

Homeostasis

The kidney is one of the major organs involved in whole-body homeostasis. Among its homeostatic functions are acid-base balance, regulation of electrolyte concentrations, control of blood volume, and regulation of blood pressure. The kidneys accomplish these homeostatic functions independently and through coordination with other organs, particularly those of the endocrine system. The kidney communicates with these organs through hormones secreted into the bloodstream.

Acid-base balance

The kidneys regulate the pH, by eliminating H ions concentration called augmentation mineral ion concentration, and water composition of the blood.

By exchanging hydronium ions and hydroxyl ions, the blood plasma is maintained by the kidney at a slightly alkaline pH of 7.4. Urine, on the other hand, is acidic at pH 5 or alkaline at pH 8.

The pH is maintained through four main protein transporters: NHE3 (a sodium-hydrogen exchanger), V-type H-ATPase (an isoform of the hydrogen ATPase), NBC1 (a sodium-bicarbonate cotransporter) and AE1 (an anion exchanger which exchanges chloride for bicarbonate). Due to the polar alignment of cells in the renal epithelia NHE3 and the H-ATPase are exposed to the lumen (which is essentially outside the body), on the apical side of the cells, and are responsible for excreting hydrogen ions (or protons). Conversely, NBC1 and AE1 are on the basolateral side of the cells, and allow bicarbonate ions to move back into the extracellular fluid and thus are returned to the blood plasma.

Blood pressure

Sodium ions are controlled in a homeostatic process involving aldosterone which increases sodium ion absorption in the distal convoluted tubules.

When blood pressure becomes low, a proteolytic enzyme called Renin is secreted by cells of the juxtaglomerular apparatus (part of the distal convoluted tubule) which are sensitive to pressure. Renin acts on a blood protein, angiotensinogen, converting it to angiotensin I (10 amino acids). Angiotensin I is then converted by the Angiotensin-converting enzyme (ACE) in the lung capillaries to Angiotensin II (8 amino acids), which stimulates the secretion of Aldosterone by the adrenal cortex, which then affects the kidney tubules.

Aldosterone stimulates an increase in the reabsorption of sodium ions from the kidney tubules which causes an increase in the volume of water that is reabsorbed from the tubule. This increase in water reabsorption increases the volume of blood which ultimately raises the blood pressure.

Plasma volume

Any significant rise or drop in plasma osmolality is detected by the hypothalamus, which communicates directly with the posterior pituitary gland. A rise in osmolality causes the gland to secrete antidiuretic hormone, resulting in water reabsorption by the kidney and an increase in urine concentration. The two factors work together to return the plasma osmolality to its normal levels.

Hormone secretion

The kidneys secrete a variety of hormones, including erythropoietin, urodilatin, renin and vitamin D.

 Pronephros

During approximately day 22 of human gestation, the paired pronephroi appear towards the cranial end of the intermediate mesoderm. In this region, epithelial cells arrange themselves in a series of tubules called nephrotomes and join laterally with the pronephric duct, which does not reach the outside of the embryo. Thus the pronephros is considered nonfunctional in mammals because it cannot excrete waste from the embryo.

Mesonephros

Each pronephric duct grows towards the tail of the embryo, and in doing so induces intermediate mesoderm in the thoracolumbar area to become epithelial tubules called mesonephric tubules. Each mesonephric tubule receives a blood supply from a branch of the aorta, ending in a capillary tuft analogous to the glomerulus of the definitive nephron. The mesonephric tubule forms a capsule around the capillary tuft, allowing for filtration of blood. This filtrate flows through the mesonephric tubule and is drained into the continuation of the pronephric duct, now called the mesonephric duct or Wolffian duct. The nephrotomes of the pronephros degenerate while the mesonephric duct extends towards the most caudal end of the embryo, ultimately attaching to the cloaca. The mammalian mesonephros is similar to the kidneys of aquatic amphibians and fishes.

Metanephros

During the fifth week of gestation, the mesonephric duct develops an outpouching, the ureteric bud, near its attachment to the cloaca. This bud, also called the metanephrogenic diverticulum, grows posteriorly and towards the head of the embryo. The elongated stalk of the ureteric bud, the metanephric duct, later forms the ureter. As the cranial end of the bud extends into the intermediate mesoderm, it undergoes a series of branchings to form the collecting duct system of the kidney. It also forms the major and minor calyces and the renal pelvis.

The portion of undifferentiated intermediate mesoderm in contact with the tips of the branching ureteric bud is known as the metanephrogenic blastema. Signals released from the ureteric bud induce the differentiation of the metanephrogenic blastema into the renal tubules. As the renal tubules grow, they come into contact and join with connecting tubules of the collecting duct system, forming a continuous passage for flow from the renal tubule to the collecting duct. Simultaneously, precursors of vascular endothelial cells begin to take their position at the tips of the renal tubules. These cells differentiate into the cells of the definitive glomerulus.

Acquired

·                     Diabetic nephropathy

·                     Glomerulonephritis

·                     Hydronephrosis is the enlargement of one or both of the kidneys caused by obstruction of the flow of urine.

·                     Interstitial nephritis

·                     Kidney stones are a relatively common and particularly painful disorder.

·                     Kidney tumors

o                     Wilms tumor

o                     Renal cell carcinoma

·                     Lupus nephritis

·                     Minimal change disease

·                     In nephrotic syndrome, the glomerulus has been damaged so that a large amount of protein in the blood enters the urine. Other frequent features of the nephrotic syndrome include swelling, low serum albumin, and high cholesterol.

·                     Pyelonephritis is infection of the kidneys and is frequently caused by complication of a urinary tract infection.

·                     Renal failure

o                     Acute renal failure

o                     Chronic renal failure

THE FORMATION OF URINE

FIGURATION, REABSORPTION, AND SECRETION

Every one of us depends on the process of urination for the removal of certain waste products in the body. The production of urine is vital to the health of the body. Most of us have probably never thought of urine as valuable, but we could not survive if we did not produce it and eliminate it. Urine is composed of water, certain electrolytes, and various waste products that are filtered out of the blood system. Remember, as the blood flows through the body, wastes resulting from the metabolism of foodstuffs in the body cells are deposited into the bloodstream, and this waste must be disposed of in some way. A major part of this "cleaning" of the blood takes place in the kidneys and, in particular, in the nephrons, where the blood is filtered to produce the urine. Both kidneys in the body carry out this essential blood cleansing function. Normally, about 20% of the total blood pumped by the heart each minute will enter the kidneys to undergo filtration. This is called the filtration fraction. The rest of the blood (about 80%) does not go through the filtering portion of the kidney, but flows through the rest of the body to service the various nutritional, respiratory, and other needs that are always present.

For the production of urine, the kidneys do not simply pick waste products out of the bloodstream and send them along for final disposal. The kidneys' 2 million or more nephrons (about a million in each kidney) form urine by three precisely regulated processes: filtration, reabsorption, and secretion.

Filtration

Urine formation begins with the process of filtration, which goes on continually in the renal corpuscles (Figure 3). As blood courses through the glomeruli, much of its fluid, containing both useful chemicals and dissolved waste materials, soaks out of the blood through the membranes (by osmosis and diffusion) where it is filtered and then flows into the Bowman's capsule. This process is called glomerular filtration. The water, waste products, salt, glucose, and other chemicals that have been filtered out of the blood are known collectively as glomerular filtrate. The glomerular filtrate consists primarily of water, excess salts (primarily Na+ and K+), glucose, and a waste product of the body called urea. Urea is formed in the body to eliminate the very toxic ammonia products that are formed in the liver from amino acids. Since humans cannot excrete ammonia, it is converted to the less dangerous urea and then filtered out of the blood. Urea is the most abundant of the waste products that must be excreted by the kidneys. The total rate of glomerular filtration (glomerular filtration rate or GFR) for the whole body (i.e., for all of the nephrons in both kidneys) is normally about 125 ml per minute. That is, about 125 ml of water and dissolved substances are filtered out of the blood per minute. The following calculations may help you visualize how enormous this volume is. The GFR per hour is:

125 ml/min X 60min/hr= 7500 ml/hr.

The GFR per day is:

7500 ml/hr X 24 hr/day = 180,000 ml/day or 180 liters/day.

Now, see if you can calculate how many gallons of water we are talking about. Here are some conversion factors for you to consider: 1 quart = 960 ml, 1 liter = 1000 ml, 4 quarts. = 1 gallon. Remember to cancel units and you will have no problem.

Now, what we have just calculated is the amount of water that is removed from the blood each day - about 180 liters per day. (Actually it also includes other chemicals, but the vast majority of this glomerular filtrate is water.) Imagine the size of a 2-liter bottle of soda pop. About 90 of those bottles equals 180 liters! Obviously no one ever excretes anywhere near 180 liters of urine per day! Why? Because almost all of the estimated 43 gallons of water (which is about the same as 180 liters - did you get the right answer?) that leaves the blood by glomerular filtration, the first process in urine formation, returns to the blood by the second process - reabsorption.

Reabsorption

Reabsorption, by definition, is the movement of substances out of the renal tubules back into the blood capillaries located around the tubules (called the peritubular copillaries). Substances reabsorbed are water, glucose and other nutrients, and sodium (Na+) and other ions. Reabsorption begins in the proximal convoluted tubules and continues in the loop of Henle, distal convoluted tubules, and collecting tubules (Figure 3). Let's discuss for a moment the three main substances that are reabsorbed back into the bloodstream.

Large amounts of water - more than 178 liters per day - are reabsorbed back into the bloodstream from the proximal tubules because the physical forces acting on the water in these tubules actually push most of the water back into the blood capillaries. In other words, about 99% of the 180 liters of water that leave the blood each day by glomerular filtration returns to the blood from the proximal tubule through the process of passive reabsorption.

Active transport is the movement of all types of molecules across a cell membrane against its concentration gradient (from low to high concentration). In all cells, this is usually concerned with accumulating high concentrations of molecules that the cell needs, such as ions, glucose and amino acids. If the process uses chemical energy, such as from adenosine triphosphate (ATP), it is termed primary active transportSecondary active transport involves the use of an electrochemical gradient. Active transport uses cellular energy, unlike passive transport, which does not use cellular energy. Active transport is a good example of a process for which cells require energy. Examples of active transport include the uptake of glucose in the intestines in humans and the uptake of mineral ions into root hair cells of plants. 

 Specialized trans-membrane proteins recognize the substance and allows it access (or, in the case of secondary transport, expend energy on forcing it) to cross the membrane when it otherwise would not, either because it is one to which the phospholipid bilayer of the membrane is impermeable or because it is moved in the direction of the concentration gradient. The last case, known as primary active transport, and the proteins involved in it as pumps, normally uses the chemical energy of ATP. The other cases, which usually derive their energy through exploitation of an electrochemical gradient, are known as secondary active transport and involve pore-forming proteins that form channels through the cell membrane.

Sometimes the system transports one substance in one direction at the same time as cotransporting another substance in the other direction. This is called antiportSymport is the name if two substrates are being transported in the same direction across the membrane. Antiport and symport are associated with secondary active transport, meaning that one of the two substances is transported in the direction of its concentration gradient utilizing the energy derived from the transport of second substance (mostly Na+, K+ or H+) down its concentration gradient.

Particles moving from areas of low concentration to areas of high concentration (i.e., in the opposite direction as the concentration gradient) require specific trans-membrane carrier proteins. These proteins have receptors that bind to specific molecules (e.g., glucose) and thus transport them into the cell. Because energy is required for this process, it is known as 'active' transport. Examples of active transport include the transportation of sodium out of the cell and potassium into the cell by the sodium-potassium pump. Active transport often takes place in the internal lining of the small intestine.

Plants need to absorb mineral salts from the soil or other sources, but these salts exist in very dilute solution. Active transport enables these cells to take up salts from this dilute solution against the direction of the concentration gradient.

 

Model of active transport

ATP hydrolysis is used to transport hydrogen ions against the electrochemical gradient (from low to high hydrogen ion concentration). Phosphorylationof the carrier protein and the binding of a hydrogen ion induce a conformational (shape) change that drives the hydrogen ions to transport against the electrochemical gradient. Hydrolysis of the bound phosphate group and release of hydrogen ion then restores the carrier to its original conformation.

Primary active transport, also called direct active transport, directly uses energy to transport molecules across a membrane.

Most of the enzymes that perform this type of transport are transmembrane ATPases. A primary ATPase universal to all life is the sodium-potassium pump, which helps to maintain the cell potential. Other sources of energy for Primary active transport are redox energy and photon energy (light). An example of primary active transport using Redox energy is the mitochondrial electron transport chain that uses the reduction energy of NADH to move protons across the inner mitochondrial membrane against their concentration gradient. An example of primary active transport using light energy are the proteins involved in photosynthesis that use the energy of photons to create a proton gradient across the thylakoid membrane and also to create reduction power in the form of NADPH.

 

The nutrient glucose (blood sugar) is entirely reabsorbed back into the blood from the proximal tubules. In fact, it is actively transported out of the tubules and into the peritubular capillary blood. None of this valuable nutrient is wasted by being lost in the urine. However, even when the kidneys are operating at peak efficiency, the nephrons can reabsorb only so much sugar and water. Their limitations are dramatically illustrated in cases of diabetes mellitus, a disease which causes the amount of sugar in the blood to rise far above normal. As already mentioned, in ordinary cases all the glucose that seeps out through the glomeruli into the tubules is reabsorbed into the blood. But if too much is present, the tubules reach the limit of their ability to pass the sugar back into the bloodstream, and the tubules retain some of it. It is then carried along in the urine, often providing a doctor with her first clue that a patient has diabetes mellitus. The value of urine as a diagnostic aid has been known to the world of medicine since as far back as the time of Hippocrates. Since then, examination of the urine has become a regular procedure for physicians as well as scientists.

Sodium ions (Na+) and other ions are only partially reabsorbed from the renal tubules back into the blood. For the most part, however, sodium ions are actively transported back into blood from the tubular fluid. The amount of sodium reabsorbed varies from time to time; it depends largely on how much salt we take in from the foods that we eat. (As stated earlier, sodium is a major component of table salt, known chemically as sodium chloride.) As a person increases the amount of salt taken into the body, that person's kidneys decrease the amount of sodium reabsorption back into the blood. That is, more sodium is retained in the tubules. Therefore, the amount of salt excreted in the urine increases. The process works the other way as well. The less the salt intake, the greater the amount of sodium reabsorbed back into the blood, and the amount of salt excreted in the urine decreases.

Secretion

Now, let's describe the third important process in the formation of urine. Secretion is the process by which substances move into the distal and collecting tubules from blood in the capillaries around these tubules (Figure 3). In this respect, secretion is reabsorption in reverse. Whereas reabsorption moves substances out of the tubules and into the blood, secretion moves substances out of the blood and into the tubules where they mix with the water and other wastes and are converted into urine. These substances are secreted through either an active transport mechanism or as a result of diffusion across the membrane. Substances secreted are hydrogen ions (H+), potassium ions (K+), ammonia (NH3), and certain drugs. Kidney tubule secretion plays a crucial role in maintaining the body's acid-base balance, another example of an important body function that the kidney participates in.

The organs involved in regulation of external acid-base balance are the lungs are the kidneys.

The lungs are important for excretion of carbon dioxide (the respiratory acid) and there is a huge amount of this to be excreted: at least 12,000 to 13,000 mmols/day.

In contrast the kidneys are responsible for excretion of the fixed acids and this is also a critical role even though the amounts involved (70-100 mmols/day) are much smaller. The main reason for this renal importance is because there is no other way to excrete these acids and it should be appreciated that the amounts involved are still very large when compared to the plasma [H+] of only 40 nanomoles/litre.

There is a second extremely important role that the kidneys play in acid-base balance, namely the reabsorption of the filtered bicarbonate. Bicarbonate is the predominant extracellular buffer against the fixed acids and it important that its plasma concentration should be defended against renal loss.

In acid-base balance, the kidney is responsible for 2 major activities:

·                     Reabsorption of filtered bicarbonate: 4,000 to 5,000 mmol/day

·                     Excretion of the fixed acids (acid anion and associated H+): about 1 mmol/kg/day.

Both these processes involve secretion of H+ into the lumen by the renal tubule cells but only the second leads to excretion of H+ from the body.

The renal mechanisms involved in acid-base balance can be difficult to understand so as a simplification we will consider the processes occurring in the kidney as involving 2 aspects:

·                     Proximal tubular mechanism

·                     Distal tubular mechanism

Proximal Tubular Mechanism

The contributions of the proximal tubules to acid-base balance are:

·                     firstly, reabsorption of bicarbonate which is filtered at the glomerulus

·                     secondly, the production of ammonium

 

In physiologyreabsorption or tubular reabsorption is the flow of glomerular filtrate from the proximal tubule of the nephron into the peritubular capillaries, or from the urine into the blood. It is termed "reabsorption" because this is technically the second time that the nutrients in question are being absorbed into the blood, the first time being from the small intestine into the villi. This happens as a result of sodium transport from the lumen into the blood by the Na+/K+ ATPase in the basolateral membrane of the epithelial cells. Thus, the glomerular filtrate becomes moreconcentrated, which is one of the steps in forming urine. In this way, many useful solutes (primarily glucose and convoluted tubulethrough the Bowman's capsule, return in the active transport through cotransport channelsdriven by the sodium gradient out of the nephron.

Implications of Urinary pH Changes

Depending upon the rates of the interrelated processes of acid secretion, NH4+ production, and HCO3- excretion, the pH of the urine in humans varies from 4.5 to 8.0. Excretion of a urine that is at a pH different from that of the body fluids has important implications for the body's electrolyte and acid-base economy. Acids are buffered in the plasma and cells, the overall reaction being HA + NaHCO3 → NaA + H2CO3. The H2CO3 forms CO2 and H2O, and the CO2 is expired, while the NaA appears in the glomerular filtrate. To the extent that the Na+ is replaced by H+ in the urine, Na+ is conserved in the body. Furthermore, for each H+ ion excreted with phosphate or as NH4+, there is a net gain of one HCO3- ion in the blood, replenishing the supply of this important buffer anion. Conversely, when base is added to the body fluids, the OH- ions are buffered, raising the plasma HCO3-. When the plasma level exceeds 28 meq/L, the urine becomes alkaline and the extra HCO3- is excreted in the urine. Because the rate of maximal H+ secretion by the tubules varies directly with the arterial PCO2, HCO3- reabsorption also is affected by the PCO2.

REGULATION OF NA+ & CL- EXCRETION

Na+ is filtered in large amounts, but it is actively transported out of all portions of the tubule except the thin loop of Henle. Normally, 96% to well over 99% of the filtered Na+ is reabsorbed. Most of the Na+ is reabsorbed with Cl-, but some is reabsorbed in the processes by which one Na+ ion enters the bloodstream for each H+ ion secreted by the tubules, and in the distal tubules a small amount is actively reabsorbed in association with the secretion of K+.

Regulation of Na+ Excretion

Because Na+ is the most abundant cation in ECF and because Na+ salts account for over 90% of the osmotically active solute in the plasma and interstitial fluid, the amount of Na+ in the body is a prime determinant of the ECF volume. Therefore, it is not surprising that multiple regulatory mechanisms have evolved in ter- restrial animals to control the excretion of this ion. Through the operation of these regulatory mechanisms, the amount of Na+ excreted is adjusted to equal the amount ingested over a wide range of dietary intakes, and the individual stays in Na+ balance. Thus, urinary Na+ output ranges from less than 1 meq/d on a low-salt diet to 400 meq/d or more when the dietary Na+ intake is high. In addition, there is a natriuresis when saline is infused intravenously and a decrease in Na+ excretion when ECF volume is reduced. Variations in Na+ excretion are effected by changes in the amount filtered and the amount reabsorbed in the tubules. The factors affecting the GFR, including tubuloglomerular feedback, are discussed above. Factors affecting Na+ reabsorption include the circulating level of aldosterone and other adrenocortical hormones, the circulating level of ANP and other natriuretic hormones, the amount of angiotensin II and PGE2 in the kidneys, and the rate of tubular secretion of H+ and K+.

Effects of Adrenocortical Steroids

Adrenal mineralocorticoids such as aldosterone increase tubular reabsorption of Na+ in association with secretion of K+ and H+ and also Na+ reabsorption with Cl- (see Chapter 20). When these hormones are injected into adrenalectomized animals, there is a latent period of 10-30 minutes before their effects on Na+ reabsorption become manifest, because of the time required for the steroids to alter protein synthesis via their action on DNA. Mineralocorticoids may also have more rapid membrane-mediated effects, but these are not apparent in terms of Na+ excretion in the whole animal. The mineralocorticoids act primarily on the cortical collecting ducts on P cells to increase the number of active ENaCs in the apical membranes of these cells.

In Liddle's syndrome, mutations in the genes that code for the β subunit and less commonly the γ subunit of the ENaCs cause them to become constitutively active in the kidney. This leads to Na+ retention and hypertension.

Other Humoral Effects

Reduction of dietary intake of salt increases aldosterone secretion, producing marked but slowly developing decreases in Na+ excretion. A variety of other humoral factors affect Na+ reabsorption. PGE2 causes a natriuresis, possibly by inhibiting Na+-K+ ATPase and possibly by increasing intracellular Ca2+, which in turn inhibits Na+ transport via ENaCs. Endothelin and IL-1 cause natriuresis, probably by increasing the formation of PGE2. ANP and related molecules increase intracellular cGMP, and this inhibits transport via the ENaCs. Inhibition of Na+-K+ ATPase by the other natriuretic hormone, which appears to be endogenously produced ouabain, also increases Na+ excretion. Angiotensin II increases reabsorption of Na+ and HCO3- by an action on the proximal tubules. There is an appreciable amount of angiotensin-converting enzyme in the kidneys, and the kidneys convert 20% of the circulating angiotensin I reaching them to angiotensin II. In addition, angiotensin I is generated in the kidneys.

Prolonged exposure to high levels of circulating mineralocorticoids does not cause edema in otherwise normal individuals because eventually the kidneys escape from the effects of the steroids. This escape phenomenon, which may be due to increased secretion of ANP. It appears to be reduced or absent in nephrosis, cirrhosis, and heart failure, and patients with these diseases continue to retain Na+ and become edematous when exposed to high levels of mineralocorticoids.