Got Aldosterone

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Got Aldosterone?
2
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

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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 11ß-hydroxysteroid
  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

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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

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• 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 lumen-negative 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

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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

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• It has been suggested that aldosterone regulates
  blood pressure through a number of mechanisms.

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Aldosterone and Hypertension

• Primary aldosteronism as described by Conn in
  1955 had been thought to be an uncommon cause of
  hypertension with prevalence of lt 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

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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

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Aldosterone and Hypertension

• Mosso et al. took gt 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

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Stage 1 140-159/90-99 Stage 2 160-179/100-109 Stag
e 3 gt180/110
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• 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

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Aldosterone and Kidney Fibrosis

• Aldosterones 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.

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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

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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

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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

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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.

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J Am Soc Nephrol 19 14591462, 2008
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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