SODIUM
REGULATION
HEMOSTASIS
Nima Behmard 01-76
Na+ BALANCE
o Major cation of ECF
o All these mentioned factors are related to each other.
Amount of Na+ in ECF
Volume of ECF
Plasma volume
Blood volume
Blood pressure
ALDOSTERONE
o mineralocorticoid steroid hormone
o primary function is to elevate blood pressure
o Aldosterone's primary target is the nephron, the functional unit of the kidney
o release from glomerulosa cells (GC) in the cortex of the adrenal glands:
• extracellular K+ concentration
• the renin-angiotensin system (RAS)
Renin
o An aspartic protease that hydrolyzes the liver-released proenzyme angiotensinogen to
produce angiotensin I → cleaved further by carboxypeptidase angiotensin-converting
enzyme (ACE) to produce active angiotensin II (ANG II).
o ANG II induces the GC to produce aldosterone.
o Klotho protein (KL), ACTH, natriuretic peptides (NPs), and the circadian clock are all
capable of regulating aldosterone production
o These are causes juxtaglomerular cells (JGC) in the afferent arteriole of the nephron to
release renin into the circulation
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Reduced blood pressure
The sympathetic nervous system
reduced NaCl supplied to the distal tubule
o When the juxtaglomerular apparatus's macula densa cells detect a low NaCl content in
the filtrate → they release paracrine signals that activate JGC.
Angiotensin II
o Angiotensin II is the primary signal for increased aldosterone secretion by adrenal
glomerulosa cells
o Actions on the kidney
o By constricting renovascular smooth muscle it increases vascular resistance in the
kidney and hence decreases renal blood flow and glomerular filtration
o Therefore, by decreasing glomerular filtration, angiotensin II decreases sodium and
water excretion
Angiotensin II
o Cardiovascular effects
• Stimulation of angiotensin II receptors in vascular smooth muscle results in
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increased intracellular calcium concentrations and sustained vasoconstriction
Acts directly on cardiac myocytes to increase calcium influx and therefore cardiac
contractility
o Central nervous system effects
• Angiotensin II, acting both as a hormone and as a neurotransmitter, stimulates
thirst, appetite for sodium, and secretion of ADH through actions exerted on the
hypothalamus
Angiotensin II
Angiotensin II
Mechanisms of Aldosterone
Secretion
o the primary signaling molecules that govern aldosterone synthesis are
o ANG II, ACTH, and K+
o These inputs can function in two ways: acute and chronic.
The acute reaction
o occurs within minutes
o leads in an increase in aldosterone owing to the activation of enzymes involved in the
o
biosynthesis process
the mobilization of cholesterol
whereas the chronic reaction
o impact occurs hours later
o includes changes in gene expression
Aldosterone Biosynthesis
Pathway
o Aldosterone is synthesized in the mitochondria and endoplasmic reticulum of zona
glomerulosa cells in the adrenal cortex.
o The cholesterol precursor can be derived from a combination of sources:
o mobilization of cholesteryl esters stored in lipid droplets by cholesteryl ester hydrolase
o de novo synthesis in the endoplasmic reticulum
o receptor-mediated uptake
o internalization of plasma lipoprotein-derived cholesterol.
Aldosterone Biosynthesis Pathway
o The free cholesterol is transported by the steroidogenic acute regulatory (StAR) protein
from the outer to the inner mitochondrial membrane, which is the early rate-limiting step
in steroidogenesis.
o In the inner mitochondrial membrane, steroidogenesis is initiated by the side-chain
cleavage of cholesterol catalyzed by CYP11A1 to yield the steroid precursor,
pregnenolone.
o Pregnenolone passively diffuses to the endoplasmic reticulum where it is converted to
progesterone by type II 3β-hydroxysteroid dehydrogenase (3βHSD2).
o Progesterone is then hydroxylated to 11-deoxycorticosterone by CYP17.
o The final late rate-limiting steps of aldosterone biosynthesis are completed in the
mitochondria, where aldosterone synthase (CYP11B2) catalyzes the conversion of 11deoxycorticosterone to corticosterone and subsequently to aldosterone.
Aldosterone Biosynthesis Pathway
Adrenocorticotropin hormone
o ACTH (Adrenocorticotropin hormone) from the pituitary gland stimulates the adrenal
cortex.
o After stimulation of the adrenal cortex by the ACTH, the process of steroidogenesis starts
from the cholesterol.
o The pituitary gland (ACTH) is stimulated by the Hypothalamic hormone (Corticotropinreleasing factor (CRH).
o ACTH initially enhances GC cell aldosterone synthesis; however, with continued induction
by ACTH, the GC phenotype shifts to that of zona fasciculata, resulting in a reduction in
aldosterone synthesis.
Adrenocorticotropin hormone
o Cellular mechanisms involved in the biosynthesis of adrenal steroids. The cellular
mechanisms that underlie adrenal steroidogenesis are initiated by activation of the
adrenocorticotropic hormone (ACTH) receptor and angiotensin II type I (ATIIR) receptor
by ACTH and angiotensin II, respectively. Steroidogenesis is also initiated by changes in
serum potassium levels through the specific expression of potassium channels in the
zona glomerulosa. This is followed by the activation of second messengers, which initiate
cholesterol mobilization. Cholesterol can be obtained from LDL and HDL lipid carriers,
lipid droplets, or de novo synthesis. Unesterified cholesterol is transported to the
mitochondria, where cleavage by CYP11A1 is the first step of steroidogenesis. Tissuespecific expression in the various zones of the adrenal cortex leads to aldosterone and
cortisol biosynthesis. Abbreviations: 3β HSD, 3β-hydroxysteroid dehydrogenase; HSL,
hormone-sensitive lipase; LDLR, low-density lipoprotein receptor; SR-BI, scavenger
receptor class BI.
Adrenocorticotropin hormone
Klotho protein
o is a single-pass transmembrane type 1 glycoprotein
o has been identified as an anti-aging molecule since serum KL levels decline with age.
o Decreased serum KL levels have been linked to age-related diseases include
• coronary artery
• disease,
• atherosclerosis,
• myocardial infarction,
• and hypertension.
o In mice, there was a negative connection between serum KL and aldosterone levels.
Natriuretic peptides (NPs)
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are primarily released by the heart
aid in vasodilation and fluid regulation.
can operate as endocrine components and have autocrine and paracrine signaling
capacities.
They have been postulated to control aldosterone secretion because to their function
in blood pressure regulation.
peptides in crude cardiac extracts were able to suppress GC aldosterone synthesis
even when stimulated by ANG II and ACTH.
atrial NPs inhibit the aldosterone response to ANG II in rats.
Human men experienced similar outcomes.
Natriuretic peptides (NPs)
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The simultaneous injection of modest amounts of atrial NPs with either ACTH or ANG
II had no effect on blood pressure or aldosterone levels.
Another method NPs control blood pressure is through influencing renal filtration and
renin release.
Renin secretion was significantly reduced in isolated rabbit afferent arterioles and
suspended JGC subjected to NPs.
In vivo investigations in dogs support these findings, with atrial NP infusion increasing
renal flow, glomerular filtration rate, salt and potassium excretion, while decreasing
blood pressure and renin production.
These findings imply that RAS and NPs may function as endogenous antagonists.
Circadian clock
o
The molecular clock is comprised of a transcriptional loop in which heterodimers of the
transcription factors BMAL1 (brain and muscle ARNT-like protein 1) and CLOCK
(circadian locomotor output cycles kaput) stimulate the transcription of the Per and
Cry genes. Accumulating PER and CRY proteins feedback to inhibit the BMAL1–
CLOCK heterodimer. Rhythmic, antiphase expression of two nuclear receptors, ROR
and REV-ERB, maintain the circadian pattern of gene expression of Bmal1 and Clock
via RORE response elements. The output of the molecular clock is rhythmic expression
of a wide range of genes, dubbed clock-controlled genes, that typically contain E-box
(BMAL1/CLOCK), D-box (DBP or E4BP4) or ROR (ROR or REV-ERB) response
elements and thus follow a circadian pattern of expression coupled to circadian
oscillations of these transcription factors. Cheng et al.3 demonstrate that key genes
regulating progression of proteins through the secretory pathway are CCG’s, allowing
circadian regulation of secretion of proteins that are not direct CCG’s themselves.
Circadian clock
Circadian clock
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Several physiological activities, including as blood pressure, immunological response,
and metabolism, are possibly controlled by the circadian clock via four "circadian
clock" proteins:
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period 1-3 (Per 1-3),
Bmal1,
clock cryptochrome 1-2,
and Clock.
Per1 controls ENaC expression in both an aldosterone-dependent and an
aldosterone-independent way.
also controls the expression of other genes involved in renal Na+ reabsorption in a
coordinated manner.
They include Per1-mediated Na+-K+-ATPase upregulation via Fxyd5 and endothelin 1
downregulation, which is a possible ENaC inhibitor.
Per-1 regulates not only the downstream targets of aldosterone, but also the plasma
levels of aldosterone.
Circadian clock
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Per1 knockout mice had lower levels of aldosterone and 3-dehydrogenase isomerase.
Male mice appear to be more vulnerable to the negative phenotypes of Per-1 KO than
female mice.
Deoxycorticosterone pivalate (DOCP), an aldosterone analog, elevated mean arterial
pressure and disrupted normal circadian blood pressure in Per-1 KO mice on a high
salt diet.
These effects are not seen in female Per-1 KO mice treated similarly.
Endothelin 1 can explain this discrepancy.
Male mice fed a high salt diet and given DOCP showed a lower night/day ratio of
urine ET-1 and different ET-1 and ET-1 receptor gene expression than female mice.
Circadian clock
The baseline profile from the circadian
study shows a trough in aldosterone
during sleep and a peak in the morning
upon awakening. Data were standardized
to each participant's time of sleep and
then averaged.
Circadian clock
Pathology
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Disorders of plasma sodium are the most common electrolyte disturbances in clinical
medicine,
yet
they
remain
poorly
understood.
Severe
hyponatraemia
and
hypernatraemia are associated with considerable morbidity and mortality, however,
and even mild hyponatraemia is associated with worse outcomes when it complicates
conditions such as heart failure, although which is cause and which effect is often
uncertain. Distinguishing the cause(s) of hyponatraemia may be challenging in clinical
practice, and controversies surrounding its management remain.
Pathology
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Sodium imbalances are widespread, especially in hospital patients and the elderly.
Mild sodium problems might be asymptomatic and self-limiting, while severe sodium
disorders have a high morbidity and fatality rate.
The reasons of sodium imbalance are frequently iatrogenic and hence preventable.
Assessing hydration status and monitoring sodium levels in plasma and urine are
critical steps in determining the etiology of hyponatraemia.
The history will generally reveal the cause of hypernatraemia.
For the treatment of salt problems, there is little evidence from randomized controlled
studies.
Slow sodium correction is typically safe, as long as clinical status and plasma sodium
are closely monitored.
Hyponatraemia
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If a clear precipitating reason is present, such as vomiting or diarrhoea, when both
sodium and total body water are low, and especially if the patient (usually elderly) is
taking diuretics, determining the etiology of hyponatraemia may be easy. In hospital
practice, determining the reason is frequently more difficult. Hyponatraemia nearly
invariably reflects an excess of water relative to sodium, most typically as a
consequence of dilution of total body sodium subsequent to increases in total body
water (water overload), but sometimes occasionally as a result of total body sodium
depletion in excess of contemporaneous body water losses. The clinical categorization
of hyponatraemia based on the extracellular fluid volume status of the patient, as
hypovolaemic, euvolaemic, or hypervolaemic.
Classification of hyponatraemia
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Hypovolaemia
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Hypervolaemia
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Extrarenal loss, urine sodium <30 mmol/l
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Urine sodium <30 mmol/l
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Dermal losses, such as burns, sweating
Gastrointestinal
losses,
such
as
vomiting, diarrhoea
Pancreatitis
Renal loss, urine sodium >30 mmol/l
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Congestive cardiac failure
Cirrhosis with ascites
Nephrotic syndrome
Urine sodium >30 mmol/l
• Chronic renal failure
Diuretics
Salt wasting nephropathy
Cerebral salt wasting
Mineralocorticoid deficiency (Addison's
disease)
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Paradoxical retention of sodium and
water despite a total body excess of
each; baroreceptors in the arterial
circulation
perceive
hypoperfusion,
triggering an increase in arginine
vasopressin release and net water
retention.
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Classification of hyponatraemia
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Euvolaemia
Urine sodium >30 mmol/l
Syndrome of inappropriate antidiuretic hormone
secretion (SIADH)
Hypothyroidism
Hypopituitarism (glucocorticoid deficiency)
Water intoxication:
Primary polydipsia
Excessive administration of parenteral hypotonic
fluids
Post-transurethral prostatectomy
Hypernatraemia
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Hyponatraemia is far more prevalent than hypernatraemia.3 It represents either a net
water loss or a hypertonic sodium increase, with the resulting hyperosmolality. Only
sudden and significant elevations in plasma sodium concentrations over 158-160
mmol/l cause severe symptoms. Importantly, in individuals with altered mental state
or hypothalamic lesions affecting their feeling of thirst (adipsia), as well as babies and
the elderly, the sensation of extreme thirst that protects against severe
hypernatraemia may be absent or decreased. Non-specific symptoms such as
anorexia, muscular weakness, restlessness, nausea, and vomiting are common in the
early stages. More severe symptoms include changed mental state, lethargy,
irritability, stupor, or coma. Acute brain shrinkage can result in vascular rupture, which
can result in cerebral bleeding and subarachnoid hemorrhage.
Classification of hyponatraemia
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Hypovolaemia
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Hypervolaemia
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Dermal losses—for example, burns,
sweating
Gastrointestinal losses—for example,
vomiting, diarrhoea, fistulas
Diuretics
Postobstruction
Acute and chronic renal disease
Hyperosmolar non-ketotic coma
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Iatrogenic (hypertonic saline, tube
feedings, antibiotics containing sodium,
or hypertonic dialysis)
Hyperaldosteronism - Typically mildly
elevated sodium ∼147 mmol/l, so rarely
a clinical problem
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Euvolaemia
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Diabetes insipidus (central, nephrogenic, or gestational)
Hypodipsia
Fever
Hyperventilation
Mechanical ventilation
Sources
•
Agarwal, R. (2010). Regulation of circadian blood pressure: from mice to astronauts.
Curr. Opin. Nephrol. Hypertens. 19, 51–58. doi: 10.1097/MNH.0b013e3283336ddb
•
Anantharam, A., and Palmer, L. G. (2007). Determination of epithelial Na+ channel
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70. doi: 10.1085/jgp.200609716
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Anderson, J. V., Struthers, A. D., Payne, N. N., Slater, J. D., and Bloom, S. R. (1986).
Atrial natriuretic peptide inhibits the aldosterone response to angiotensin II in man.
Clin. Sci. 70, 507–512.
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Arima, S., Kohagura, K., Xu, H. L., Sugawara, A., Abe, T., Satoh, F., et al. (2003).
Nongenomic vascular action of aldosterone in the glomerular microcirculation. J. Am.
Soc. Nephrol. 14, 2255–2263. doi: 10.1097/01.ASN.0000083982.74108.54
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Arteaga, M. F., Wang, L., Ravid, T., Hochstrasser, M., and Canessa, C. M. (2006). An
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•
Reynolds, R. M., Padfield, P. L., & Seckl, J. R. (2006). Disorders of sodium balance.
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