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
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.
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.
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.
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).
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.
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.
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.
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.
The kidneys secrete a variety
of hormones,
including erythropoietin, urodilatin, renin and vitamin D.
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.
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.
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.
·
Hydronephrosis is the enlargement of one or
both of the kidneys caused by obstruction of the flow of urine.
·
Kidney stones are a relatively common and
particularly painful disorder.
·
Kidney tumors
·
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.
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:
Now, what we have just
calculated is the amount of water that is removed from the blood each
day - about
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
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 transport. Secondary 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 antiport. Symport 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
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 physiology, reabsorption 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.