Week 2: Regulation of bp, Kidney in HTN

Question 1

Summarize the chain of events known as pressure natriuresis- the effects of arterial bp on renal excretion of NaCl.

Answer 1

In response to increased arterial bp

• increased renal perfusion pressure–>decreased NaCl reabsorption in the PT (mechanism unclear)–>more NaCl to macula densa –>TGF –>afferent arteriole constriction –>keeps GFR from increasing
• decrease in Na and volume reabsorption in PT and DCT culminates in pressure induced natriuresis, diuresis.

Question 2

Diagram the 6 feedback relationships connecting ECFV, BP, and AngII/SNS.

Answer 2

1. BP –AngII/SNS
   - Increased bp–>decreased renin and SNS
   - decreased bp–>increased AngII and SNS–>vasoconstriction
2. BP – ECFV
   - increased BP–>decreased NA reabsorption
   - decreased BP–>increased CO and tissue vasoconstriction
3. ECFV – AngII, SNS
   - Increased ECFV–>decreased renin and SNS, increased ANP
   - decreased ECFV–>increased AngII, SNS–>increased Na reabsorption.

Question 3

Summarize the homeostatic mechanisms governing “escape” from mineralocorticoid excess: transport along nephron, endocrine adjustments.

Answer 3

• escape from sodium retaining effects of increased aldosterone
• Aldosterone increases Na reabsorption along CD, persistent and uncorrected–>increased ECF volume
• increases in mean arterial bp and central venous pressure
  1. response to central venous pressure increases
• ->atrial stretch–>ANP increases and SNS decreases–>decreased RAS, ADH, decreased IMCD Na transport–>decreased tubular Na reabsorption along nephron except aldosterone sensitive region of CD
  2. response to increases in mean arterial bp
• ->increased renal perfusion pressure–>decreased renin, RAS, pressure/natriuresis–>decreased tubular Na reabsorption except in aldosterone sensitive region of CD

Question 4

What is Gitelman’s syndrome?

Answer 4

• mutation leading to inactive NCC co transporter in DCT.
• Hypotension, hypokalemia, and alkalosis
• mimicked by thiazide diuretics

Question 5

What is Bartter’s syndrome?

Answer 5

• mutations leading to inactivation of transporters in TALH: can be NaK2Cl, apical K+ channels, basolateral Cl- channels
• hypotension, hypokalemia, alkalosis

Question 6

Describe pseudohypoaldosteronism (PHA).

Answer 6

Type 1 autosomal dominant
-loss of function mutations in mineralocorticoid receptor with high aldosterone
-leads to hypotension, hyperkalemia, and acidosis
Type 1 autosomal recessive
-loss of function mutations in ENac subunits with similar but more severe symptoms because ENac is affected

Question 7

What are lesions that cause hypertension? List 1

Answer 7

1. hyperaldosteronism: excess NaCl reabsorption in distal nephron
2. pseudohyperaldosteronism type 2: mutations in kinase cascade or degradation pathways that lead to activation (phosphorylation) of DCT NCC
3. defect of 11B-OH SD: glucocorticoids saturate also-receptors. excess Na reabsorption. (excess licorice consumption inhibits this enzyme and can do the same)
4. Liddle’s syndrome: mutation in beta or y subunit of epithelial Na channel, leads to prolonged channel retention in apical membrane and open in–>excess Na reabsorption in CDs
5. Mineralocorticoid receptor mutation: binds progesterone–>HTN in pregnant females
6. Renovascular HTN: renal artery stenosis of one kidney–>decreased renal perfusion–>increased renin from stenotic kidney–>increased AngII and aldosterone–>unregulated increased Na reabsorption from both kidneys

Question 8

What are lesions that cause hypertension? List 2

Answer 8

7. Renin secreting tumor in JGA–>high AngII generated
8. elevated plasma angiotensinogen
9. adducin mutation
10. WNK and SPAK kinase mutations–>constitutive activation of NCC by phosphorylation=Gordan’s syndrome
11. Calcineurin inhibitors: immunosuppressive drugs that inhibit calcineurin, preventing dephospho rylation of NCC, leading to increased NCC-P and activation of Na reabsorption in DCT

Question 9

Of the renal mechanisms, what is the most important in physiologic control of bp?

Answer 9

-regulation of Na excretion and blood volume

Question 10

What are mechanisms that regulate renal renin secretion?

Answer 10

1. perfusion pressure in renal afferent arterioles
2. SNS
3. macula densa mechanism
4. prostaglandins
5. angiotensin II exerts a negative feedback
6. serum glucose

Question 11

What are effects of renal sympathetic nerves?

Answer 11

• a1: vasoconstriction of afferent arteriole
• b1: JP apparatus–>release of renin
• a1: proximal tubule and TAL-increased Na and water reabsorption via activation of Na/K ATPase