Lecture 12
PHYSIOLOGY OF THE KIDNEYS AND THE
URINARY TRACT II.
HORMONAL CONTROL OF THE KIDNEY FUNCTION
Fluid regulation in the body is achieved by controlling the intake and
excretion of water and sodium ions which has partly neural, partly endocrine
character.
Water is continuously lost by lungs, body surface, sweat glands, urination
and defecation, and replenished by body metabolism and by drinking. Water
metabolism of the body is controlled by a system of neural and endocrine
mechanisms accompanied by the subjective feeling of THIRST. Furthermore,
fluid regulation is achieved by controlling the intake and excretion of water and
sodium ions.
Part of the drinking is not related to water deficit. This is called
spontaneous drinking. It is necessary to prevent dry mouth, to adjust body
temperature, to prevent anticipated water deficit (food, sweating). Also, the flavor
of the drink and its variety are involved.
Drinking and eating are usually tightly linked. Disruption of one disrupts the
other. Thereis dehydratation-induced anorexia, quickly reversed after rehydration.
Hormonal effects are involved.
There are two mechanisms of thirst, osmometric and volumetric,
although in the living organism, the double-depletion theory of thirst states that
both mechanisms are usually involved in the control of the water balance at
once.
A. Osmometric Thirst
The osmometric thirst is due to the loss of body water. There is an
increase in the osmotic pressure of the extracellular, and ultimately also the
intracellular, fluids. Due to an increase in osmotic pressure of the
extracellular fluid, water is drawn from the cells and the blood volume does not
decrease.
Osmotic receptors are still mysterious. They have been located in
hypothalamus. Magnocellular neurosecretory cells here may also serve as
osmoreceptors. Some osmoreceptors are also found in the region of the portal vein,
in the stomach and in the gut, but their role is uncertain and they probably do not
initiate drinking.
The receptors are specifically excited or inhibited by the hypertonic and
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hypotonic solutions. Little is known about the mechanism by which this is achieved.
They may actually be sodium receptors.
When the osmotic receptors are activated, the suprachiasmatic,
supraoptic and paraventricular nuclei of hypothalamus produce vasopressin
which is transported to the posterior pituitary and released from it.
B. Volumetric Thirst
The volumetric thirst is also called hypovolemic or extracellular thirst. The
volumetric thirst is caused by a decrease of the volume of circulating blood
and/or extracellular fluid. It is usually caused by the loss of blood by bleeding.
The osmotic pressure of the blood does not change. The volumometric receptors
(baroreceptors) are in the heart atria and in the kidney (juxtaglomerular
apparatus). Atriopeptin, a peptide hormone released from the heart, is
decreased, and renin from the kidney is increased when the volume of the
blood decreases. Renin further catalyzes the formation of a hormone angiotensin
from the precursor angiotensinogen in the blood plasma. Angiotensin protects
the level of water in the organism, and also acts as a dipsogen (thirst-producing
agent) in the hypothalamus.
Termination of Drinking
Amount of water consumed by the organism is not rigorously regulated.
We drink excess fluids, and pass the excess off as dilute urine. The satiation
of thirst is gradual, the individual stops drinking before the deficit had been made
up. Later drinking gradually replaces lost fluid. The nuclei of septum probably
function as inhibitors of drinking. Their destruction causes overdrinking
(hyperdipsia).
MULTIPLE CONTROL OF THE KIDNEY FUNCTION
Neuronal Function
The function of the kidneys is, in the first place, controlled by the nervous
system. Reflexes originating in the arterial baroreceptors in the aortic arch and in
the carotid sinus may regulate the plasma volume.
The kidneys receive extensive sympathetic innervation which can alter
kidney water and sodium excretion. Sympathetic activity causes:
*
The constriction of renal arterioles;
*
Increased tubular reabsorption of water and sodium;
*
Stimulation of renin release and increased angiotensin II and
aldosterone formation.
Hormonal Function
Over twenty hormones or humoral agents are involved in the kidney
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function. Among them are steroids, thyroid hormones, peptides and local
mediators such as prostaglandins and bradykinin.
Extrarenal sensors are necessary to control all nephron functions.
RENIN-ANGIOTENSIN SYSTEM (RAS)
The renin - angiotensin system is mainly involved in the control of volumetric
thirst. It is composed of the enzyme renin, the plasma protein angiotensinogen
(which is converted by renin into angiotensin) and an adrenal cortical steroid,
aldosterone.
Angiotensinogen
Angiotensinogen is the only known substrate for the enzyme renin. Although
the most abundant source of plasma angiotensinogen is the liver, other analytical
techniques have confirmed the angiotensinogen mRNA expression in a wide range
of tissues, including the kidney, brain, vascular tissue, adrenal gland, placenta and
leucocytes.
Renin
Renin is a proteolytic glycoprotein enzyme which degrades blood plasma
angiotensinogen to angiotensin. It is a highly specific aspartyl proteinase. It is
released by the juxtaglomerular apparatus (JG). The granulated cells producing
renin are present also in the media layer of the afferent and efferent arterioles of
the glomerulus and in some cells of proximal tubules.
The release of renin increases when the arterial blood pressure in the kidney
decreases. This enzyme is synthesized in the cells as a large preprorenin
molecule. Renin is activated (split from the prohormone) in the granules of
the granulated cells. These cells contain also angiotensinogen.
All of the regulating factors of the renin-angiotensin system feed back on
renin secretion from the JG cells. The following factors are involved in renin
release:
*
renal sympathetic nerves which activate renin secretion.
*
low intrarenal perfusion pressure which stimulates renin secretion.
*
distal tubule sodium load: low sodium and chloride in the distal
tubule
stimulate the release of renin.
*
low plasma potassium stimulates renin secretion.
Pathology of Renin
Overproduction or underproduction of renin results in disturbances
of body fluid and circulatory homeostasis. Goldblatt in his famous experiment
(1934) put a clamp on one or both renal arteries, thus reduced the pressure in the
renal arteries and induced hypertension. Further work led to the discovery of
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the renin-angiotensin system. Recent development of inhibitors of renin,
angiotensin converting enzyme, and angiotensin receptor improved the treatment
of the hypertensive disease.
ANGIOTENSIN
The prohormone angiotensinogen is one of the plasma globulins.
Angiotensinogen is the only known substrate cleaved by renin. It is released
from the liver.
The first product of the degradation of angiotensinogen is angiotensin I, a
decapeptide. Angiotensin I probably does not have any physiological effects.
Angiotensin I is converted to angiotensin II, an octopeptide, by an
angiotensin converting enzyme (ACE, kininase II, dipeptidyl carboxypeptidase).
The converting enzyme is a membrane-bound protein anchored to the
endothelium of many blood vessels.
Angiotensin III is des-Asp1-angiotensin II. It produces some arteriolar
constriction, and its aldosterone-stimulating activity is high. It predominates in
hypothalamus and medulla. It has binding sites in this region.
Angiotensin (1-7) is an important component of the renin-angiotensin
system. It is produced directly from angiotensin I. It has a vasodepressor function.
In addition, angiotensin-(1-7) alters tubular sodium and bicarbonate reabsorption,
decreases Na+-K+-ATPase activity, induces diuresis.
Inhibitors of ACE (enalapril, spirapril etc.) are used for the treatment of
hypertension.
Angiotensin receptors
The angiotensin receptors exist in the cell membranes of the smooth muscles
of the blood vessels, in the heart, in the autonomic nervous system, in the adrenal
cortex, in the kidney, in the gastrointestinal tract and in the brain. Two types of
receptors have been recognized, termed AT1 and AT2. The AT1 receptor effect is
mediated by G proteins whereas the AT2 effects are not. Most actions of
angiotensin II are mediated by the AT1 receptor type. AT2 receptor is involved
mainly in the growth, proliferation and differentiation of tissues.
In many tissues, there are nuclear receptors for angiotensin which induce the
synthesis of mRNA coding for the proteins of the renin/angiotensin system. It has
been hypothesized that this locally produced angiotensin sustains the general
response to the same hormone.
In the hypothalamus, angiotensin II induces thirst and drinking.
Angiotensin Functions
Circulating angiotensin controls drinking, aldosterone secretion and
vasopressin release.
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* It induces a dipsogenic response. Its iontophoretic administration
to the supraoptic nucleus causes a dramatic increase of neuronal discharges. The
threshold effective dose in the subfornical organ is 0.1 - 1.0 picogram. Lesion
of the subfornical organ reduces angiotensin-induced drinking. OVLT(organum
vasculosum laminae terminalis) is the most sensitive region of the brain to
angiotensin II, 50 fg (femtograms) produces a drinking response here
* Also, it increases blood pressure through arteriolar vasoconstriction,
Both systolic and diastolic pressure increases. Angiotensin II is four times as
potent as noradrenaline.
* Angiotensin II plays a central role for maintenance of GFR and Na+
balance particularly in volume depletion, when Angiotensin II preferentially
increases the resistance of efferent arterioles as compared to afferent arterioles,
enhancing the glomerular perfusion pressure. In addition, AngII enhances tubular
reabsorption of sodium in proximal tubules directly and indirectly as a consequence
of glomerulotubular balance. Angiotensin II also stimulates Na reabsorption in the
collecting ducts by stimulating the release of aldosterone from the adrenal cortex.
*it stimulates sodium appetite and natriuresis.
*Circulating angiotensin II enhances renal sodium retention both by a
direct action on the kidney and by stimulating aldosterone secretion.
MINERALOCORTICOIDS
The most important mineralocorticoid is aldosterone. It induces renal
reabsorption of sodium and therefore sodium retention with some polydipsia,
increased blood volume and increased ECF volume. Under the effect of
aldosterone, sodium is conserved and only as little as a few milligrams a day may
be excreted. On the other hand, the disappearance of aldosterone causes a loss of
up to 20 g of sodium per day. Sodium reabsorption is also influenced by
aldosterone in the sweat glands, salivary glands, and intestinal glands. All this
prevents loss of sodium.
Retention of sodium may induce edema.
Also, aldosterone induces an increased tubular secretion of potassium
with subsequent hypokalemia and muscle weakness due to hyperpolarization of
the membranes. Hydrogen ion excretion by the kidney is also promoted. This
leads to alkalosis. The exchange takes place in the distal tubules and in the
collecting ducts.
The receptors for aldosterone are in the cytoplasm of the kidney tubules.
After the receptors combine with the hormone, the complex moves to the cell
nuclei. Messenger RNA synthesis in these cells is increased. This mRNA
codes for the sodium channels and enzymes of sodium and potassium transport.
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The increased sodium reabsorption takes place in about 30 minutes to two hours.
If mineralocorticoids are administered, the volume of extracellular
fluid tends to increase. The retained fluid leads to pressure diuresis and
increased loss of water and salt (aldosterone escape).
The excessive loss of potassium ions under the influence of aldosterone
causes alterations in nerve and muscle action potentials. The transmission of
action potentials is blocked.
Control of Aldosterone Secretion
The following control factors are involved:

ACTH and other pituitary factors

Directly by sodium ions in the circulating blood and ECF

potassium ion concentration in ECF;

renin - angiotensin system;

sodium in ECF;
HORMONES OF POSTERIOR PITUITARY
Vasopressin and oxytocin are present in the organism long before the
emergence of the vertebrate posterior pituitary.
VASOPRESSIN
Vasopressin (VP) is also called antidiuretic hormone (ADH). It is a
peptide hormone formed by a ring of five amino acids and a tail of three amino
acids.
Synthesis of Vasopressin
Vasopressin is synthesized from the glycoprotein propressophysin which is
a precursor of vasopressin and of its carrier protein, neurophysin. It is a
glycoprotein. It is synthesized in the magnocellular and partly in the parvocellular
neurons of the suprachiasmatic, supraoptic and paraventricular nuclei of the
hypothalamus, together with oxytocin. Each of these two hormones is
synthesized in different neurons. There are also numerous vasopressin-containing
cells in the bed nucleus of stria terminalis, the amygdala, locus coeruleus and the
dorsomedial nucleus of the hypothalamus.
Half-life of vasopressin in the tissues is about 20 minutes.
Transport of Vasopressin
Vasopressin is transported by axoplasmic flow to the posterior pituitary,
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released from the nerve endings and removed from the pituitary by blood flow.
Neuronal firing induces the release. In the posterior pituitary, there is an
enormous arborization of the axons, approximately 2000 terminals per a single
neurosecretory cell (Nordmann, 1977). Vasopressin is released directly from the
nerve endings. The pituicytes, cells of the posterior pituitary, do not store
vasopressin as claimed previously, and their function is actually unknown. They
may be involved in vasopressin release.
Beside the median eminence and posterior pituitary, vasopressin is
transported into various brain regions, mainly into the limbic system, the
medulla and the spinal cord, less into the cortex and cerebellum.
Peripheral Functions
The major peripheral function of vasopressin is to conserve water, mainly
by facilitating the reabsorption of water from the urine in the collecting ducts of
the kidney. 2 nanograms are enough to elicit the effect. A family of
water-transporting proteins (water channels, aquaporins) has been identified,
consisting of small hydrophobic proteins expressed widely in epithelial and
nonepithelial tissues. One of these water channels, aquaporin-2, has been shown to
be the target for short-term regulation of collecting duct water permeability by
vasopressin. In addition, two collecting duct water channels, aquaporin-2 and
aquaporin-3, are targets for long-term regulation by vasopressin through effects on
the water channel proteins. Vasopressin acts through insertion and removal of
aquaporin-2 into the inner medullary collecting ducs apical membranes.
Vasopressin also increases smooth muscle tone in arterioles. But, the
blood pressure in a normal individual does not increase much due to a decrease
in cardiac output.
Pathology
A defect of vasopressin synthesis is diabetes insipidus. It may be induced
by the destruction of pituitary stalk or neurohypophysis. Its most important
feature is polyuria, 20 - 25 liters per day. Polyuria is accompanied by
polydipsia. Without sufficient water supply, a circulatory failure may appear
very soon. Sometimes there are intervals of remission.
A model of diabetes insipidus has been found in the inbred strain of
Brattleboro rats which are genetically deficient in vasopressin (West Brattleboro
in Vermont). These rats show:
- diabetes insipidus
- defect of learning
ATRIAL NATRIURETIC FACTORS
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The natriuretic peptide system consists of at least four endogenous ligands:
* atrial natriuretic peptide,
* brain natriuretic peptide,
* C-type natriuretic peptide = the endothelial component of the natriuretic
peptide system.
* dendroaspis natriuretic peptide where the understanding is incomplete.
The mammalian heart also serves as an endocrine organ. The myocytes
of the atria have secretory granules which are released directly into the
circulation. These granules are also present in the heart ventricle and in the brain.
They contain a family of peptides known as atrial natriuretic factors (ANP),
atriopeptins. These cells are presumably mechanoreceptors measuring the
tension of the atrial wall. An increase in the intravascular volume increases the
tension of the atrial wall and thus,

release of atriopeptins through mechano-sensitive ion channels.

The release depends also on adrenergic stimulation

The release of the atrial natriuretic peptides increases with the
increasing heart rate.

Modulation of natriuretic peptide release appears to be linked to local
generation of prostaglandins and

intracellular calcium.
In general, they may be involved in the future treatment of heart diseases.
The natriuretic peptide system is implicated in the pathophysiology of hypertension,
congestive heart failure, atherosclerosis and renal diseases.
Structure and Synthesis
The atrial natriuretic peptides are probably synthesized in the Golgi
apparatus of the cardiac myocytes (myoendocrine cells) from a preprohormone.
A number of biologically active ANP's varying in length are released from the
preprohormone. In cardiac hypertrophy, they are also secreted by ventricular
myocytes.
All atriopeptins have a 17 amino acid ring and differ only in the length
of N- and C- terminal extensions. The predominantly circulating form of ANP
has 28 amino acids, and is called atriopeptin 28 or cardionatrin.
A-type and B-type are localized not only in the specific granules of these
myoendocrine cells but also in many other organs including the brain, adrenal
medulla, and kidney.
There is also a synthesis of natriuretic peptides in the kidney glomerular
epithelial cells. This urodilatin is localized in the kidney, differentially processed,
and secreted into the urine.
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ANP Receptors
The population of ANP receptors is functionally heterogeneous.
There are three types of receptors:
* ANP-A receptor which is guanyl cyclase A;
* ANP-B which is guanyl cyclase B;
* ANP-C which is a clearance receptor.
The atriopeptins are removed from the circulation by clearance receptors
in various organs. The atriopeptins are then degraded by an endopeptidase.
Natriuretic peptides (NP) act as ligands of the guanylyl cyclase family of
receptors. The NP binding site on these receptors is extracellular and the guanylyl
cyclase and protein kinase domains are intracellular. The guanylyl cyclase receptor
catalyzes the synthesis of the second messenger molecule, cGMP, which activates
protein kinase.
Functions in the Body
ANP bind with specific receptors in the kidneys, adrenal gland, and
vascular system to regulate natriuresis, diuresis and smooth muscle relaxation:
* Natriuresis and diuresis appear within minutes after the injection.
The ANP probably influence the kidney function in the proximal tubule,
descending and ascending Henle's loop and medullary collecting tubule. Nitrous
oxide produced in the tubules may be involved in the modulation of the function.
* Atrial natriuretic peptide (ANP) has varied effects on cardiac
electrophysiologic parameters including heart rate, intraatrial conduction time, and
refractory period. ANP's vagoexcitatory and sympathoinhibitory actions may be
responsible for some of these effects.
* Due to their effect on the vascular smooth muscles, they decrease
arterial blood pressure, cardiac filling pressure, cardiac output and a
translocation of fluid from plasma to the interstitial fluid space.
* The pulmonary smooth muscles are relaxed as well, and so are the
intestinal smooth muscles. ANP has been found in these tissues as well.
Urodilantin
In urine, another peptide was isolated, urodilatin, which has 32 amino
acids identical to alpha-ANP, but with an N-terminal extension. It is produced
in the kidney tubules and collecting ducts. After release from distal tubular kidney
cells into the tubular lumen, URO binds to luminal receptors (NPR-A) in the
collecting duct. A sodium channel is formed which induces diuresis and natriuresis.
It probably binds to receptors in renal collecting ducts. This part of the
nephron is involved in ANP-mediated regulation of sodium and water
reabsorption. It is natriuretic, and is not degraded by enzymes that deactivate
atriopeptin. It is not clear whether urodilatin is the only renal natriuretic
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peptide. URO is a putative drug for several related diseases.
Pathology of ANP
* ANP are increased in congestive heart failure, renal failure and always
when there is fluid retention, but its role is not clear. It may have antihypertensive
effect.
* ANP are involved in hypertension caused by excess salt in the diet.
Other hormones affecting kidney
The guanylin family of bioactive small peptides consists of three
endogenous peptides, including guanylin, uroguanylin and lymphoguanylin.
These small cysteine-rich peptides activate cell-surface guanylin cyclase receptors,
thus modulating cellular function via the intracellular second messenger, cyclic
GMP. Guanylin and uroguanylin are produced within the intestinal mucosa to serve
in regulation of intestinal fluid and electrolyte absorption. Uroguanylin serves as a
postprandial natriuretic hormone.
In the kidney, uroguanylin stimulates urine flow and excretion of sodium,
chloride, and potassium. Uroguanylin serves in an endocrine axis linking the
intestine and kidney where its natriuretic and diuretic actions contribute to the
maintenance of Na+ balance following oral ingestion of NaCl.
Functions of ADH
ADH is bound to a specific receptor (V2 receptor) located in the basolateral
membrane of the cells, a G protein is activated, activates adenyl cyclase, cAMP
formed, specific cytoplasmic vehicles insert water channels into the apical
membrane. If ADH is low, endocytosis of water channels follows.
MICTURITION
= the fluid from the kidney flows to the renal pelvis, ureter, urinary bladder.
The urinary bladder holds about 500 ml
* two sphincters are:
- Internal sphincter is an internal continuation of the bladder wall, they
consist of smooth muscle.
- external sphincter is a ring of skeletal muscle controlled by spinal
motoneurons.
* micturition is a simple spinal reflex, there is both conscious and unconscious
control.
- stretch of the bladder activates two sets of neurons - parasympathetic
leading to the smooth muscles are excited. Smooth muscles contract, increase the
pressure.
- somatic motor neurons are inhibited.
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RENAL ACID - BASE CONTROL
General points
1. The body is constantly threatened by acid resulting from diet and metabolism. The
stability of blood pH is maintained by the concerted action of chemical buffers, the
lungs, and the kidneys.
2. Numerous chemical buffers (e.g., HCO3 -/CO2, phosphates, proteins) work
together to minimize pH changes in the body. The concentration ratio (base/acid) of
any buffer pair, together with the pK of the acid, automatically defines the pH.
3. The bicarbonate/CO2 buffer pair is effective in buffering in the body because its
components are present in large amounts and the system is open.
4. The respiratory system influences plasma pH by regulating the PCO2 by changing
the level of alveolar ventilation. The kidneys influence plasma pH by getting rid of
acid or base in the urine.
5. Renal acidification involves three processes: reabsorption of filtered HCO3 -,
excretion of titratable acid, and excretion of ammonia. New HCO3 - is added to the
plasma and replenishes depleted HCO3 - when titratable acid (normally mainly
H2PO4 -) and ammonia (as NH4 +) a re excreted.
6. The stability of intracellular pH is ensured by membrane transport of H+ and
HCO3 -, by intracellular buffers (mainly proteins and organic phosphates) and by
metabolic reactions.
7. Respiratory acidosis is an abnormal process characterized by an accumulation of
CO2 and a fall in arterial blood pH. The kidneys compensate by increasing the
excretion of H+ in the urine and adding new HCO3 - to the blood, thereby
diminishing the severity of the acidemia.
8. Respiratory alkalosis is an abnormal process characterize by an excessive loss of
CO2 and a rise in pH. The kidneys compensate by increasing the excretion of
filtered HC_thereby diminishing the alkalemia.
9. Metabolic acidosis is an abnormal process characterized by a gain of acid (other
than H2CO3) or a loss of HCO3-. Respiratory compensation is hyperventilation,
and renal compensation is an increased excretion of H+ bound to u nary buffers
(ammonia, phosphate).
10. Metabolic alkalosis is an abnormal process characterized by a gain of strong base
or HCO3 - or a loss of acid (other than H2CO3). Respiratory compensation is
hypoventilation and renal compensation is an increased excretion of HCO3 -.
11. The plasma anion gap is equal to the plasma [Na+] - [Ct - [HCO3 -] and is most
useful in narrowing down possible causes of metabolic acidosis.
12.The kidneys must generate 1 mmol of new HCO3- per kg body weight each day.
13. New bicarbonate is produced when NH4+ and H2PO4+ are excreted.
14. Only kidney excretes acid or alkali on a continuing basis.
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15. there are two components of renal generation of HCO3- :
- indirect reabsorption of filtered HCO3- which is achieved primarily by proximal
H+ secretion;
- generation of new HCO3- which is achieved primarily by NH4+ production and
excretion.
REABSORPTION OF FILTERED HCO3- is the first component of renal regulation of plasma HCO3- , preventing the loss
of a large quantity of filtered HCO3- occurs primarily in the proximal tubule (PCT)
- the PCT has a high capacity to secrete H+ but cannot generate steep [H+]
gradients.
- molecules of HCO3- disappear from the tubular fluid and reappear in the blood.
- most HCO3- is reabsorbed as a result of H+ secretion.
a. Key features of reabsorption of filtered HCO3-(1) H+ and HCO3- are produced in the proximal tubule cells when CO2 and H2O
combine to form H2CO3, catalyzed by the intracellular carbonic anhydrase. H+ is
secreted into the lumen via the Na+ - H+ exchange mechanism in the luminal
membrane. The HCO3- is reabsorbed.
- Na+ is transported on a Na+/ H+ antiporter. For one Na+ reabsorbed, one H+
must be secreted into the lumen. Level of Na+ in the cells is very low, therefore,
antiporter works. There is Na+-K-+ ATPase in the basolateral membrane of the
cells.
(2) In the lumen, the secreted H+ combines with filtered HCO3- to form H2CO3which dissociates to CO2 and H2O, catalyzed by the brush border carbonic
anhydrase. CO2 and H2O diffuse into the cell to start the cycle again. If the
catalysis does not occur, indirect reabsorption is retarded and HCO3- appears in
urine.
(3) There is net reabsorption of filtered HCO3- .
GENERATION OF NEW HCO3* New HCO3- is generated together with excretion of titratable acid and the
excretion of NH4+.
* This process takes place in the distal tubule.
Excretion of H+ as titratable acid (H2PO4- ), non-volatile (fixed)
- is a mechanism for excreting fixed H+ produced from catabolism of proteins and
phospholipids.
a. H+ and HC03- are produced in the cell from CO2 and H2O. The H+ is secreted
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into the lumen by an H+ -ATPase, and the HCO3- is reabsorbed into the blood
("new" HCO3-). The secreted H+ combines with filtered HPO4- to form H2PO4- ,
which is excreted as titratable acid.
- H+ -ATPases have a low capacity, but can generate steep [H+] gradients because
luminal membrane has tight junctions.
b. This process results in net secretion of H+ and net reabsorption of newly
synthesized HCO3-.
c. As a result of H+ secretion, the pH of urine becomes progressively lower, the
minimum urinary pH is 4.4.
Excretion of H+ as NH4+
- is another mechanism for excreting fixed H+ produced from protein catabolism
of protein and phospholipid.
- for every NH4+ excreted, one HCO3- is produced and added to the body.
Ammoniagenesis
NH3 is produced in renal cells from glutamine. It diffuses down its concentration
gradient into the lumen. Glutamine is released from proteins, metabolized to
glucose or CO2 via TCA cycle, ATP is generated when NH3 is formed.
- glutamine has to enter mitochondria. This is a rate-limiting step.
- phosphate - dependent glutaminase is needed.
- glutamine enters into mitochondria more in chronic metabolis acidosis and
hypokalemia.
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