SM 196a - Sodium

Question 1

Describe the pathophysiology of glucocorticoid-remediable aldosteronism

Answer 1

Basically, every time the body signals to upregulate cortisol release, aldosterone is released too

• Unequal crossing over leads to chimeric gene between aldosterone synthetase and 11-beta-hydroxylase
• The aldosterone synthetase gene falls under the control of the 11-beta-hydroxylase enzyme
  
  • Normally 11-beta-hydroxylase regulates cortisol, not aldosterone synthetase
• The result is that ACTH secreted from the pituitary promotes aldosterone release (normally aldosterone is under the control of ANG-II)
  
  • Results in aldosterone excess
• Remediable by glucocorticoids because increased glucocorticoids reduces ACTH secretion from the pituitary (due to feedback inhibition)
  
  • Clinical feature, not necessarily a long-term treatment

Question 2

Would blocking aldosterone receptors help to treat Liddle syndrome?

Why not?

Answer 2

No

Liddle syndrome causes increased ENaC activity independent of aldosterone

Question 3

Which part of the kidney tubule is sensitive to Angiotensin II?

What is the effect?

Answer 3

Proximal tubule

Angiotensin II -> increased Na+ reabsorption in the proximal tubule

Question 4

Atrial stretch decreases in response to low ECF

What compensatory mechanisms does this initiate?

Answer 4

• Decreased ANF release
  
  • Increased Na+ reabsorption in the collecting duct

=> Decreased urinary Na+ excretion

Question 5

What is the effect of a mutation in 11-beta-hydroxysteroid dehydrogenase?

Answer 5

• Cortisol cannot be converted to cortisone
• Cortisol mimicks aldosterone and effects increase Na+ reabsorption in the cortical collecting duct
• Results in apparent mineralocorticoid excess

Question 6

What causes Liddle syndrome?

Answer 6

An activating mutation in the epithelial sodium channel ENaC

-> increased Na+ reabsorption (even if inappropriate physiologically)

Question 7

What are the mediators of Na+ reabsorption in the proximal tubule?

Answer 7

• Higher oncotic pressure in the peritubular capillaries than in the tubule
• Angiotensin II
• Norepinephrine

Question 8

What is the inheritance of glucocorticoid-remediable aldosteronism?

Answer 8

Autosomal dominant

Question 9

What causes apparent mineralocorticoid excess?

Answer 9

Mutation in the 11-beta-hydroxysteroid dehydrogenase

• Cortisol cannot be converted to cortisone
• Cortisol mimicks aldosterone and effects increase Na+ reabsorption in the cortical collecting duct
• Results in apparent mineralocorticoid excess

Question 10

NaCl delivery to the macula densa decreases in response to low ECF

What compensatory mechanisms does this initiate?

Answer 10

• Increased renin release
  
  • Increased Angiotensin II production
    
    • Efferent arteriole constriction
      
      • Increased filtration fraction
      • Increased peritubular oncotic pressure
        
        • => Decreaed urinary Na+ excretion
• Decreased tubuloglomerular feedback
  
  • Afferent arteriole relaxation (dilation)
• Afferent arteriole relaxation (dilation) + efferent arteriole constriction
  
  • => Restoration of GFR

Question 11

What causes pseudohypoaldosteronism I?

Answer 11

LOF mutations in ENaC

-> Decreased Na+ reabsorption -> hypotension

Aldosterone is very high to promote Na+ reabsorption, but ENaC is not responsive