Nine Flashcards
(16 cards)
Describe the function of PTH especially its effects on the kidney. Describe the molecular mechanisms.
Parathyroid hormone (PTH) is primarily responsible for regulating
the plasma concentration of calcium. The calciumsensing
receptor (CaSR) is a G-protein–coupled receptor that
senses the extracellular calcium concentration. CaSR is expressed
on parathyroid gland cells, where it displays an inverse
sensitivity to the circulating concentration of calcium. For
example, low-serum calcium increases the secretion of PTH
and vice versa. PTH exerts its renal effects by activating several
signaling pathways, in particular, protein kinase A and
protein kinase C. In the distal tubule, PTH increases the reabsorption
of calcium by stimulating the expression of TRPV5.
PTH also interacts with receptors (PTH1r) on proximal tubular
cells resulting in inhibition of NPT and, hence, renal phosphate
reabsorption (see Fig. 6.6). An additional effect of
PTH is to increase the synthesis of calcitriol by activating
the renal 1α-hydroxylase (Fig. 9.1).
Where is ADH synth. and secreted? What effects does it have in the kidney and what are the molecular mechanisms of these effects? What regulates the secretion of ADH?
Vasopressin (antidiuretic hormone, ADH) is a polypeptide hormone
synthesized in the supraoptic (SON) and paraventricular
nuclei (PVN) in the hypothalamus. ADH is synthesized in the
cell bodies of magnocellular neurons located in the PVN and
SON and migrates along the supraoptic-hypophyseal tract to
the posterior lobe of the pituitary (Fig. 9.2).
ADH increases the water permeability of the luminal
membrane of the cortical and medullary collecting duct allowing
osmotic equilibration with the surrounding interstitium
(see Fig. 7.6). ADH also plays an important role in the generation
of a hypertonic medulla by increasing the permeability of the inner medullary collecting duct to urea. The antidiuretic
effect of ADH is mediated by vasopressin-2 receptors (V2R),
which are coupled to adenylate cyclase through a heterotrimeric
G-protein. Another class of ADH receptors, V1R, stimulates
vascular smooth muscle cells and increases vascular
resistance.
A number of factors are known to modulate the secretion
of ADH, in particular, the plasma osmolality (via osmoreceptors)
and intravascular volume.
Where are osmoreceptors located and what do they respond to? What is their response?
Osmoreceptors are located in the lamina terminalis near the hypothalamus.
The plasma sodium concentration is the primary determinant
of ADH release, since sodium salts are the major extracellular
osmoles. The osmoreceptors are exquisitely sensitive to
changes in plasma osmolality, responding to alterations in plasma
osmolality of as little as 1%. In humans, the osmotic threshold for
ADH release is 280-290 mOsm/kg of H2O (Fig. 9.3). The system
is so efficient that plasma osmolality usually does not vary by more than 1% despite wide fluctuations in water intake.
Osmolality also influences thirst. Hyperosmolality increases
water intake. The osmotic threshold for thirst is 2-5 mOsm/kg
H2O higher than that for ADH release.
Explain how volume depletion leads to ADH release. What receptors are involved? How does it differ from the osmolality response?
Volume depletion is a potent stimulus of ADH secretion. If
severe (>5%-10% decrease), volume depletion can override
the suppression of ADH induced by a low plasma osmolality.
Parasympathetic afferent nerves in the carotid sinus baroreceptors
appear to mediate this response. The sensitivity of
volume receptors is different than that of osmoreceptors.
Osmoreceptors respond to alterations in plasma osmolality of as little as 1%, in comparison, small reductions in volume or
pressure have little effect on ADH release. However, a decline
in volume of 5%-15% can lead to a marked rise in ADH secretion
resulting in circulating hormone levels that substantially
exceed those induced by hyperosmolality (Fig. 9.4). Although,
the major stimuli for ADH secretion are hyperosmolality and
volume, there are a number of other factors, which may influence
ADH secretion (Table 9.1).
Describe the causes of hyponatremia.
Hyponatremia is an extremely common electrolyte
disorder characterized by water retention and increased
circulating levels of ADH. Since the plasma osmolality
is low in this clinical condition, other factors must
override the effects of hypoosmolality on ADH secretion.
Table 9.1 includes the most common factors that can
produce an increase or decrease in ADH. Importantly, in
pathophysiologic states the prevailing level of ADH reflects
the combined effects of multiple variables (some of which
may increase ADH and others that can suppress it).
What things stimulate ADH? Inhibit it?
Stimulate ADH Hyperosmolality Volume depletion Nausea Pain Pregnancy Hypoglycemia Pneumonia HIV infection Early brain injury Many drugs
Inhibit ADH
Hypoosmolality Volume expansion Ethanol Atrial natriuretic peptide Opiates Late brain injury Norepinephrine Tolvaptan
Where does aldosterone exert its effect? What is its effect? How does it carry it out? What causes aldosterone secretion? How?
Aldosterone acts primarily in the distal nephron (specifically
the CS and CCD). Aldosterone increases the reabsorption of
sodium and secretion of potassium. Aldosterone exerts its
effect within the cell through activation of specific cytosolic
receptors, which interact with nuclear DNA (see Fig. 8.5).
Aldosterone plays an important role in the maintenance of
volume and potassium balance via its effect on sodium and
potassium excretion. Thus, it is appropriate that angiotensin II
(whose production varies inversely with volume) and hyperkalemia
are major stimuli for aldosterone secretion. Potassium
stimulates aldosterone secretion via a direct effect on the zona
glomerulosa cells in the adrenal gland. The zona glomerulosa
cells are sensitive to increments in the plasma potassium concentration
of as little as 0.1-0.2 mEq/L.
Describe aldosterone escape.
If aldosterone is administered chronically to a normal subject,
sodium retention (which expands the extracellular volume)
and potassium loss are observed. However, after a weight gain
of approximately 3 kg a spontaneous diuresis ensues, which
halts further volume expansion. This phenomenon is referred
to as aldosterone escape. At least two factors contribute to
aldosterone escape. The first is an increase in the secretion
of atrial natriuretic peptide (secondary to volume expansion)
and secondly an elevation in systemic blood pressure. An
increase in blood pressure raises intraglomerular hydrostatic
pressure and increases GFR. The rise in GFR promotes sodium
excretion in the urine. This phenomenon is also referred to as
pressure-natriuresis.
What causes ANP to be released? Where is it released from? What are its functions ?
Expansion of the extracellular volume normally induces an
appropriate loss of sodium and water in the urine. Crosscirculation
experiments have shown that the natriuretic response is mediated, at least in part, by humoral factors.
One such factor is atrial natriuretic peptide (ANP). ANP is
released from myocardial cells in the atria in response to volume
expansion. ANP exerts two major effects, direct vasodilatation,
which lowers systemic blood pressure, and enhanced
urinary excretion of sodium (see Fig. 8.8).
How do kidneys regulate Ca ion homeostasis and bone remodeling? Describe the life cycle of Vitamin D, specifically what happens in the kidneys. How is calcitriol synth regulated? What happens to bones in chronic kidney disease? How?
The kidneys regulate calcium ion homeostasis and bone
remodeling through their effects on the metabolism of vitamin
D (see Fig. 9.5). After absorption in the small intestine
or nonenzymatic synthesis in the skin from 7-dehydrocholesterol,
vitamin D3 (cholecalciferol) is transported to the liver bound to vitamin D-binding protein (DBP). Cholecalciferol
is metabolized via the hepatic enzyme 25-hydroxylase to
25-hydroxyvitamin D (calcidiol). Calcidiol circulates to the
kidneys, bound to DBP, and is filtered at the glomerulus (see
Fig. 6.9). The protein complex is reabsorbed in the proximal
tubule via receptor-mediated endocytosis. Megalin and
cubulin are essential in mediating the uptake of this complex.
Mutations of megalin are associated with calcidiol excretion
in the urine and vitamin D deficiency. The proximal tubular
epithelial cells contain the enzyme 1-α hydroxylase, which
hydroxylates calcidiol, producing 1,25 dihydroxyvitamin D
(calcitriol). The regulation of calcitriol synthesis is modulated
by the plasma concentration of calcium (low), phosphate
(low), and PTH (high), which act to stimulate its production.
Calcitriol biosynthesis is suppressed by hypercalcemia, hyperphosphatemia
and by the plasma concentration of calcitriol
itself (negative feedback loop). When calcitriol production is
suppressed, the renal 24 hydroxylase enzyme is induced and
24,25 dihydroxyvitamin D becomes the predominant metabolite
of 25- hydroxyvitamin D. 24,25 dihydroxyvitamin D is
generally believed to be inactive.
Chronic kidney disease is characterized by vitamin D
deficiency and abnormal bone turnover. Bone disease
is one of the most frequent complications observed in
patients with advanced kidney failure. Administration of
vitamin D compounds is common in this setting.
Aside from the kidney, where else can calcitriol be produced? What 3 major organs does calcitriol target and what is its function in each? What is the molec. mechanism?
While the kidney is the principal site for calcitriol production,
extrarenal calcitriol may be produced in some clinical
conditions. For example, cancers and granulomatous disorders,
such as tuberculosis and sarcoidosis, may produce
excess calcitriol. These conditions are often accompanied by
increased serum calcium.
In its target tissues, calcitriol functions, to a large extent,
as a classical steroid hormone. Current models of calcitriol
action suggest that 1,25 dihydroxyvitamin D enters the cell,
binds to its cytosolic receptor, and translocates to the nucleus
where gene transcription is induced. Circulating calcitriol
exerts its major effects on three target organs:
1. The intestine, where it augments absorption of calcium
and to a lesser extent phosphorus.
2. The skeleton, where it stimulates osteoclast activity and
bone remodeling.
3. The distal convoluted tubule, where it augments the
reabsorption of calcium via TRPV5.
Calcitriol is also produced locally by many tissues and
appears to play a role in cell growth and differentiation.
What is EPO? What is its function? How does it do it? What happens to it in chronic kidney disease? Where is EPO produced specifically? How is EPO synth regulated?
Erythropoietin (EPO) is a glycoprotein hormone responsible
for the regulation of red blood cell formation. The gene encoding human erythropoietin is located on chromosome 7
and encodes a 193-amino acid polypeptide, which is cleaved
during secretion to a 165-amino acid mature protein. The
importance of renal synthesis of EPO is highlighted by the
universal occurrence of anemia in the setting of chronic kidney
disease and the observation that parenteral injection of
EPO completely corrects the anemia.
Following the cloning of the EPO gene in 1985, EPO has
been produced in abundant quantities with recombinant DNA
technology and applied to the treatment of patients with renal
failure with dramatic success. Unlike several other hematopoietic
growth factors, EPO is largely lineage-specific, influencing
almost exclusively the growth of erythroid precursor cells
(Fig. 9.6). The colony forming unit-erythroid (CFU-E) cell
appears to be the principal cell responsive to EPO. Although
several studies have conclusively demonstrated that the major source of EPO synthesis occurs within the kidneys, the renal
cell responsible for EPO synthesis remains somewhat controversial.
RNA blot analysis suggests that EPO mRNA is predominantly
derived from peritubular fibroblasts. Transcription
of EPO mRNA is tightly coupled to the ambient oxygen tension.
For example, following the onset of hypoxia an increase
in EPO mRNA is observed within 60 minutes. A key regulatory
component of EPO gene transcription is hypoxia-inducible
factor 1 (HIF1). In hypoxic conditions, HIF1 (consists of
2 subunits, HIF-α and HIF-β) translocates to the nucleus and
binds to specific response elements involved in the transcription
of EPO. Normal oxygen tension results in hydroxylation
and degradation of HIF-α subunits (Fig. 9.7).
EPO binds to a specific transmembrane receptor (EpoR)
resulting in transphosphorylation of the Janus family tyrosine
kinase receptor 2 (JAK-2). Although bone marrow erythroid
precursors express the greatest number of EPO receptors, nonerythroid
tissues also express EpoR. In general, activation of
EpoR inhibits apoptosis. Importantly, recent studies suggest
that the anti-apoptotic effect of EPO may induce tissue regeneration.
Particularly encouraging results have emerged in
patients with spinal cord injury. Several new compounds that
exhibit a high degree of EpoR specificity have been developed
and are undergoing clinical testing for a wide range of applications
(eg, stroke and brain injury).
Describe the RAS system including where things are secreted and synthesized, what their functions are
Renin is a proteolytic enzyme secreted by the granular cells of
the afferent arteriole. It acts in plasma on a substrate of hepatic
origin, angiotensinogen, to form the decapeptide angiotensin
I. In the presence of angiotensin converting enzyme (ACE)
two amino acids are cleaved from angiotensin I to form the octapeptide, angiotensin II. Angiotensin II is a potent systemic
vasoconstrictor, stimulates aldosterone, induces thirst,
and increases the renal reabsorption of sodium. The reninangiotensin
system is one of several systems that regulate volume
homeostasis and blood pressure.
Renin secretion is primarily regulated by angiotensin II
(inhibitory), potassium (stimulatory), the sympathetic nervous
system (stimulatory), and renal perfusion pressure.
Advances in our understanding of the RAS have shed
new light on the complex nature of this system (Fig. 9.8). In
humans, it is likely that the majority of angiotensin II produced
in the heart and blood vessels is derived from pathways that do not involve ACE (eg, chymase). In addition, ACE exists as
2 isoforms (ACE-1 and ACE-2). ACE-2 produces a 7 amino
acid fragment (ANG 1-7). ANG 1-7 binds to a unique receptor
(Mas) and produces effects that are antithetical to ANG II
(vasodilation, inhibit cell growth). Finally, other angiotensin
receptor subtypes have now been well characterized. The
classic AT1 receptor mediates most of the effects commonly
attributed to angiotensin II, including an increase in cell
growth, secretion of aldosterone, and vasoconstriction. In contrast,
angiotensin receptor type 2 (AT2) exerts fundamentally
opposite effects when engaged by angiotensin II (apoptosis,
decreased cell growth, and vasodilation).
Several tissues (brain, blood vessels, heart, kidneys)
express the substrates and enzymes required to locally generate
angiotensin II. Local tissue RAS are undoubtedly important in
modulating organ function; however, their precise role in normal
physiology and pathophysiology remains unknown.
Describe the renal prostaglandins. What is their function?
The kidneys produce several biologically active substances
that exert their effects locally. These substances are rapidly
metabolized by the kidneys and, thus, do not enter the systemic
circulation. The biosynthesis of renal prostaglandins
constitutes one of the major systems that play a role in the local
regulation of renal function. Renal prostaglandins are synthesized
from fatty acid precursors (notably arachidonic acid),
which are converted by cyclooxygenase (COX1 and COX2)
to the cyclic endoperoxides TXA2, PGD2, PGF2α, PGI2, and
PGE2 (Fig. 9.9). Autoregulation of renal perfusion is mediated
in part, by local synthesis of prostaglandins. Some prostaglandins
(PGE2) augment renal excretion of electrolytes, in
particular, sodium.
What effects do NSAIDS have on the kidney? How do they do it?
The nonsteroidal anti-inflammatory drugs (NSAIDS) are
commonly used for fever and pain control. Most of these
drugs are nonselective inhibitors of renal COX1 and COX2.
They invariably decrease renal blood flow and glomerular
filtration rate, particularly in patients with preexisting
renal disease. They exert their renal hemodynamic effect
primarily via decreased renal synthesis of PGE2 (which
dilates the afferent arteriole). Overdose of these agents
can produce acute and severe reductions in renal blood
flow. In addition, these agents blunt the effects of most
antihypertensive drugs, because they promote renal
sodium retention (via inhibition of PGE2 synthesis).
Describe renal catabolism of hormones. Where does it occur? How does it occur?
The kidney is an important site for the catabolism of small and
medium sized (<50 kDa) proteins. As most peptide hormones fall within this molecular weight range, the kidneys participate
in the metabolism of numerous peptide hormones and
therefore, play an important role in endocrine homeostasis.
The renal contribution to the metabolism of many hormones is
substantial and ranges from 30%-60% of their total metabolic
clearance rate. Since the renal handling of these hormones is
characterized by high extraction (removal) from the renal circulation
while urinary excretion is negligible, it is clear that
the hormones removed by the kidneys are degraded locally.
The proximal tubule is the major site involved in the degradation
of these peptides via receptor-mediated endocytosis.
Decreased metabolism of hormones by the kidneys is important
when renal function is reduced and also in the interpretation
of assays of these hormones in blood from patients with
renal disease.
