Got Aldosterone?
Aldosterone Synthesis
• Aldosterone is produced in the zona glomerulosa of the adrenal gland
• The enzyme aldosterone synthase encoded by the gene CYP11B2 gene converts deoxycorticosterone to
aldosterone via a series of steps
•In glucocorticoid remediable aldosteronism (GRA), a chimeric gene containing the promotor sequence
of CYP11B1 and functional elements of CYP11B2 is created, resulting in aldosterone production under
the control of ACTH
Mineralocorticoid Receptor (MR)
• Aldosterone acts by diffusing into cells and attaching to a specific receptor,
mineralocorticoid receptor (MR) in the cytosol which then leads to the synthesis of
new proteins called aldosterone-induced proteins (AIPs).
• Cortisol binds to the MR receptor at equal affinity and is found in much higher
concentrations then that of aldosterone. However target cells contain 11ßhydroxysteroid dehydrogenase that converts cortisol to cortisone which is inactive.
• If 11ß-hydroxysteroid dehydrogenase is inactivated, such as in the syndrome of
apparent mineralocorticoid excess, or inhibited such as occurs in chronic
ingestion of licorice patients can present with findings similar to
hyperaldosteronism.
• MR are found in high concentrations in the renal distal nephron as well as the colon
and sweat and salvary glands, but also has been found in the heart, brain, vascular
smooth muscle, liver, and blood leukocytes
Action on Renal Tubular Cells
• Aldosterone promotes the reabsorption of NaCl and the secretion of
K+ in the principal cells in the cortical collecting tubules
• The intercalated cells in the cortex contain MR and aldosterone
enhances H+ secretion via H+-ATPase pumps in the apical
membrane.
• Na+ reabsoprtion via the principal cells causes a lumen-negative
potential which causes an electrical gradient favorable for H+
accumulation
• Aldosterone also enhances NaCl reabsorption in the distal tubule by
increasing the number of Na+-Cl- cotransporters in the luminal
membrane
• Aldosterone increases the number of open
Na+ and K+ channels in the luminal
membrane
• Increases activity of the Na+-K+-ATPase
pump in the basolateral membrane
•The AIP, serum glucocorticoid-regulated
kinase (sgk), increased number of ENaC
channels on the surface
•Nedd4 inhibits ENaC; Sgk reduces
interaction of Nedd4 and ENaC
•The movement of Na+ through its channel
ENaC is electrogenic, creates a lumennegative potential difference.
• Electroneutrality is maintained in this
setting either by passive Cl- reabsorption
via the paracellular pathway or by K+
secretion from the cell into the lumen
Inhibition and Stimulation
• Aldosterone is stimulated by a number of factors
but the most important include angiotensin II,
hyperkalemia, and ACTH.
• Angiotensin II and hyperkalemia stimulate both
the synthesis and stimulation of aldosterone
synthase in the zona glomerulosa.
• Aldosterone inhibition occurs predominantly by
ANP and hypokalemia
It has been suggested that aldosterone regulates blood pressure through a
number of mechanisms.
Aldosterone and Hypertension
• Primary aldosteronism as described by Conn in 1955
had been thought to be an uncommon cause of
hypertension with prevalence of < 1% among
hypertensive patients
• Gordon et al in early 1990s screened 52 hypertensive
pts and found that 12% of the individuals were
positive for primary aldosteronism
• In a follow up study by Gordon evaluation of 199 pts
referred to a hypertension clinic found a prevalence
of primary aldosteronism to be at least 8.5%
Aldosterone and Hypertension
• Since the early studies by Gordon multiple investigators
have confirmed a prevalence of primary aldosteronism of
5-15% in general selective hypertensive population. Two
studies in particular:
• Schwartz and Turner evaluated 118 pts with hypertension
and withdrew antihypertensive treatment. Diagnosis of
primary aldosteronism was made with 4 day salt load and
lack of suppresion of aldosterone secreation
• Primary aldosteronism was diagnosed in 13% of
individuals
Aldosterone and Hypertension
• Mosso et al. took > 600 hypertensive patients and
screened them for primary aldosteronism by
measurements of plasma aldosterone/PRA ratio
• Pts with high ratio were evaluated by fludrocortisone
suppresion testing to confirm the diagnosis of
primary aldosteronism
• Overall the prevalence of primary aldosteronism was
6.1% but increased with relation to the severity of
hypertension
Stage 1 140-159/90-99
Stage 2 160-179/100-109
Stage 3 >180/110
• Studies from separate laboratories suggest that primary aldosteronism is a common
cause of resistant hypertension, with prevalence of approximately 20%
•75% of pts in the Birmingham study had suppressed renin activity despite all pts were
on a diuretic and ACEI or ARB
•67% of pts in the Oslo study had supressed renin activity also despite use of diuretics
and ACEI or ARB.
•This suggests mineralocorticoid excess beyond the 20% of pts who were identified to
have true primary aldosteronism
Aldosterone and Kidney Fibrosis
• Aldosterone’s ability the enhance systemic and
intraglomerular capillary pressure has been favored as the
major mode of damage to the kidney
• However recent animal studies suggest that aldosterone may
have a more direct effect on the kidneys.
• In other organs such as the heart it has already been shown
that after MI excessive aldosterone production is associated
with harmful local effects that lead to fibrosis
• Aldosterone infusion in adrenalectomized rats with renal
mass ablation (a model of progressive kidney disease)
cancels the renoprotective effects of ACEI or ARBs.
Aldosterone and Kidney Fibrosis
• In vitro studies show aldosterone increased TGF-B
and fibronectin production by mesangial cells in
culture
• Aldosterone infusion for 3 days in normal rats cause
more than 2 fold increase in urinary excretion of
TGF-B
• TGF-B signaling pathways upregulate collagen
synthesis and promote fibroblast proliferation
Aldosterone and Kidney Fibrosis
• Some of the effects of TGF-B are mediated by
connective tissue growth factor (CTGF)
• CTGF stimulate proliferation of renal fibroblasts and
induce extracellular matrix synthesis
• It has been shown in vitro that aldosterone
significantly increases CTGF gene expression and
protein synthesis in cultured mesangial and proximal
tubular cells
Aldosterone and Kidney Fibrosis
• In rats adosterone has been shown to increase
reactive oxygen species (ROS) and other
proinflammatory cytokines
• ROS has been shown to induce proximal tubular cell
apoptosis as well as expansion of mesangial matrix
and enhanced cell proliferation
Aldosterone and Kidney Fibrosis
• Plasminogen activator inhibitor-1 (PAI-1) is known
to promote accumulation of extracellular matrix in
endothelial cells
• Several studies have shown that aldosterone causes
that up-regulation of PAI-1 expression independent of
TGF-B or ROS production.
J Am Soc Nephrol 19: 1459–1462, 2008
Aldosterone and Kidney Fibrosis
• Spironolactone limits the development of
glomerulosclerosis in tubulointerstitial fibrosis in rats
with streptozotocin induced diabetic nephropathy
• In Dahl salt sensitive rats, a model of hypertensive
glomerulosclerosis, eplerenone prevents podocyte
damage, proteinuria, and glomerulosclerosis
• Inihibition of aldosterone receptor also has shown in
rat models to provide renoprotection in animals with
established renal injury