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(1-5) Translational Medical Science > Trigger 3: Gordon's Hypotension Syndrome > Flashcards

Trigger 3: Gordon's Hypotension Syndrome Flashcards

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1
Q

describe the renin angiotensin aldosterone system

A

1) Renin released from kidney when mechanoreceptors- juxtaglomerular cells detects a decrease in pressure
2) Macula densa cells sense sodium and chlorine in tubular fluid- decrease in tubular NACl renin release
3) B1AR stimulation- renin release
4) Plasma angiotensinogen (made in the liver)- a zymogen- inactive precursor
5) Renin released from kidney
6) Cuts angiotensinogen angiotensin1
7) ACE from the lung (vascularized tissue) converts angiotensin 1 angiotensin II (active)
8) Angiotensin II is a powerful vasoconstrictor

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2
Q

Angiotensin causes..

A

release of aldosterone, ADH and ANP negative feedback

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3
Q

aldosterone causes

A

an increase in sodium reabsorption in nephron- increasing ECF and blood volume

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4
Q

give the key details of type 1 pseudohypoaldosteronism

A
  • autosomal dominant
  • mutations in the ENaC or MLR
  • causes loss of NA
  • also gives low K+ and Cl- and metabolic acidosis
  • aldosterone is high
  • renin is high
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5
Q

clinical sings of T1 PHA

A
  • high aldosterone and renin
  • hypotension
  • hyponatraema
  • hypokalaemia
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6
Q

why is t1 PHA a true pseudo

A

because aldosterone is high to compensate

- aldosterone looks like it would be low, but it is high

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7
Q

What is Gordon’s syndrome also known as

A

Type 2 Pseudohypoaldosteronism

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8
Q

Give key details of Gordon’s

A
  • autosomal dominant
  • caused by mutations of WNK1/4 and other enzymes
  • which leads to hyperactivity of NCC and NKCC2
  • causing excessive retention of Na, K and Cl
  • low aldosterone and renin
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9
Q

why is aldosterone low in Gordon’s

A

due tot he fact the overactive channels means more water is being retained increasing BP, therefore less aldosterone needs to be released

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10
Q

Clinical signs of Gordon’s

A
  • hypertension
  • hypernatremia
  • Hyperkalaemia
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11
Q

Gordons syndrome is also characterised by

A

short stature

intellectual impairment

dental abnormalities

muscle weakness

severe hypertension

ow fractional excretion of sodium

normal renal function

hypochloraemia metallic acidosis

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12
Q

RAAS in GS

A

In those with GS, aldosterone appears high due to high BP, but is actually is low due to the fact the mutations within the WNK pathway causing phosphorylation of ion channels, which increased absorption of ions high BP

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13
Q

Hyperkalaemia

A

increased serum potassium levels

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14
Q

Hyperchloraemia

A

increased serum chloride levels

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15
Q

what causes hyerkalaemia and hyperchloraemia

A

WNK1/4 activates NCC, NKCC1 and NKCC2

  • These are sodium/ potassium chloride co—transporter
  • Loss of function in GS
  • This leads to uninhibited activation of the transporters- impaired excretion
  • Leads to increased K+ and Cl- in the blood
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16
Q

metabolic acidosis

A

Blood is too acidic, resulting in decrease in blood pH

  • Excretion of H+ ions decreased
  • An increased in absorption of H+ ions
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17
Q

difference between metabolic acidosis and respiratory acidosis

A
  • Respiratory acidosis is cause by an increase in CO2

- Metabolic acidosis is caused by a decrease in HCO3- (not absorbing enough)

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18
Q

Metabolic-

A

caused by an imbalance in the production of acids or bases and their excretion by the kidneys

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19
Q

Respiratory-

A

caused primarily by changes in carbon dioxide exhalation due to lung or breathing disorders.

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20
Q

hypertension

A
  • Increase in salt ions results in increases osmotic potential
  • Increasing water retention
  • Increasing blood pressure
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21
Q

which genes are modified in GS

A

WNK1 and WNK4, KLHL3/ CUL3

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22
Q

What are WNKS

A
  • Novel kinases (WNK- With No Lysine)
  • Large proteins
  • Kinase domain
  • Lysine at the N terminus anchors and orientates ATP
  • The catalytic lysine in all WNK family members is located in the glycine rich B strand rather than the typical position in B strands 3 of the kinase domain, where it is found in all other protein kinases
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23
Q

WNK1

A

Normally WNK1 prevents WNK4 from interacting with Na-Cl cotransporter

24
Q

What happens when WNK1 is mutated

A

Mutations in WNK1 are intronic deletions that increase WNK1 expression

25
Q

WNK4

A
  • WNK4 acts as a negative regulator of thiazide- sensitive Na-Cl cotransporter (NCCT) function, reducing cell surface expression of NCCT
  • WNK4 also downregulates the potassium channel ROMK and epithelial chloride flux
26
Q

what happens when WNK4 is mutated?

A
  • Mutations in WNK4 are missense mutations and cause loss of function, so that WNK4 loses its ability to suppress NCCT and ROMK
  • Transporter over activity consequently leads to sodium and potassium retention
27
Q

CUL3-KLHL3 complex

A

WNK inhibitors

  • Prevent upregulation of SPAK/OSR1 signalling
  • Prevents phosphorylation of NCC less Na+/ water reabsorption reduced hypertension
28
Q

What does the CUL3-KLHL3 complex mutation do?

A

prevents the ubiquitination of WNK1/4

29
Q

animal model of KLHL3 or CUL3

A

mouse model

¥ Deletion of exon 9 from Cullin-3 (CUL3, residues 403-459: CUL3D403-459) causes pseudohypoaldosteronism type IIE (PHA2E) a severe form of familial hyperkalaemia and hypertension (FHHt)

30
Q

Phosphorylation

A

activates

31
Q

ubiquitination

A

sends to the proteome for destruction

32
Q

what happens normally

A

Under normal conditions, WNK4 protein within cells are maintained by appropriate degradation after ubiquitination by KLHL3-Cullin3 E3 Ligase.

33
Q

WNK and high blood pressure

A
  • Ubiquitination
    1. WNK1/4 acts as a substrate for CUl-3 and KHLH3 (Kelch-like 3 and Cullin 3 complex), resulting in ubiquitination of WNK1/4
    2. Ubiquitination of WNK1/4 targets the kinase for proteosomal degradation in the proteasome
    3. This prevents its phosphorylation
    4. Resulting in SPAK/OXSR1 not being phosphorylated
    5. NCC, NKCC1, NKCC2 are not activated by SPAK/OXSR1 by phosphorylation, therefore Ions do not flow into the cell and water is not retained resulting in lower blood pressure
34
Q

WNK and low blood pressure

A

WNK and Low Blood Pressure

  • Phosphorylation
    1. WNK (lysine deficient protein kinase 1 and 4) is activated by osmotic stress
    2. Phosphorylates SPAK/ OXSR1 ( sterile20 related proline-alanine-rich kinase and oxidative stress response kinase 1)
    3. SPAK/OXSR1 is activated via phosphorylation by WNK1/4 and itself goes on to phosphorylate the sodium chloride cotransporter and Na-K-Cl cotransporters
    4. Activation of NCC, NKCC1 and NKCC2 leads to influx of Na+, k+ and Cl- ions into the cell
    5. Change in osmosis results in H20 entering the DCT cells, increasing retention of water and increasing blood pressure
35
Q

WNK and gordons syndrome

A

less WNK degradation- more NCC activation

  1. Mutation in the CUL-3 and KHLH3 complex disables ubiquitination of WNK1/4
  2. Without degradation of WNK1/4 the kinases build up within the cell continually phosphorylating SPAK/OXSR1
  3. This results in over activation of SPAK/ OXSR1 leading to increased activity of transporters
  4. Ions flow into the cell, retaining water due to osmotic pressures leading to high blood pressures
36
Q

which ion channels are affected

A

NCC NKCC KCC

37
Q

Sodium chloride co-transporter (NCC)

A
  • Located on apical membrane of cells in the DCT
  • Na+Cl- cotransporter
  • NaCl influx
  • Activated WNK kinases will bind with SPAKs to phosphorylate them at thr243, then activated phosphor-SPAK then binds to NCC and phosphorylate at Thr60
  • This pNCC has increased intrinsic activity and increases Na influx
38
Q

Sodium- potassium- chloride co-transporter (NKCC)

A
  • Thick ascending limb of loop of henle

- Na+K+2Cl- cotransporter into cell

39
Q

Potassium Chloride Co-transporter

A
  • Proximal tubule

- K+ couple Cl- exporters

40
Q

utations in NCC regulators, WNK1 and WNK4

Leads to

A

over activation of NCC, NKCC, KCC’s
leads to high blood serum potassium (hyperkalaemia), increases NA reabsorption (hypernatremia)and increases Cl- (hyperchloremia).

41
Q

surveillance of GS includes

A

rutine electrolyte and blood pressure measurements

42
Q

Treatments

A

aim to keep blood pressure low and electrolytes balanced

43
Q

Preventive step

A

avoiding food high in salt and potassium

44
Q

types of therapeutics (4)

A

Thiazide diuretic
Loop diuretics
SPAK inhibitors
WNK inhibitors

45
Q

what is the most common treatment

A

thiazide diuretics

46
Q

examples of thiazide diuretics

A

e.g. Chlorothiazide, chlorothalidone, metolazone

47
Q

where do thiazide diuretics work

A

on the DCT

48
Q

how do thiazide diuretics work

A
  • Antagonists of the NCC Na+/Cl- cotransporters
    o Prevents the 10% sodium reabsorption that normally occurs in the DCT, therefore also preventing water reabsorption and so reduces BP
    ♣ Increases Calcium reabsorption, by lowering the intracellular Na+ conc, the activity of the basolateral Ca2+/Na+ increases- more calcium drawn out of urine
    ♣ Increased potassium excretion, since the increased conc of Na in the uroe means the Na/K antiporter in the collecting duct works harder
    ♣ Increases excretion of hydrogen ions which can cause metabolic alkalosis
49
Q

thiazide diuretic increases renal extraction of..

A 
¥	Sodium – like all diuretics
¥	Potassium 
¥	Hydrogen ions 
¥	(causing metabolic alkalosis) 
¥	Decreases renal excretion of: 
¥	Calcium
50
Q

effect of thiazide diuretics

A

Effectors- treats hypertension, hyperkaliemia, hypercalciuria

51
Q

limitations of thiazide diuretics

A

Limitations
- Patients with WNK4 mutation respond better than those with WNK1 mutation. Cant take if you have urinary problems, gout, severe kidney or liver disease, Addison’s disease

52
Q

loop diuretics

A
  • Inhibits NKCC2 symporters in the ascending loop of Henle
    Prevents formation of a conc gradient in the renal medulla, so there is less osmotic force to drive reabsorption of water in the collecting duct
    Can cause hypokalaemia
    Increases Na+ excretion by up to 25%
53
Q

SPAK inhibitors (in development)- blocking WNK-SPAK binding

A

− SPAK kinases upregulate chloride influx through phosphorylation of NCC and NKCC2
− SPAK-knockout mice have hypotensive phenotypes
− SPAK inhibitors, such as a SPAK-specific ATP-competitive kinase inhibitor, could be used to develop antihypertensive
− Potential to be a better therapeutic than thiazides because
o Would inhibit chloride influx through both NCC and NKCC2
o Would avoid the side effect of hypokalemia caused by thiazides and loop diuretics
− You would need to develop sufficiently selective inhibitors that do not suppress other kinases

54
Q

WNK inhibitors are in

A

clinical trials

55
Q

WNK inhibitors would work by

A
  • Inhibitors of WNK-OSR-1/SPAK NCC cascade prevents NCC causing hypertension.
  • WNK/SPAK signaling phosphorylates NCC- if this is inhibited= decreased activation of the Na-Cl cotransporter
56
Q

. A child has been diagnosed with pseudohypoaldosteronism type II (PHA II) caused by a mutation of the Cullin 3 gene and is about to commence a new form of PHA II treatment.
• State the current established treatment option for PHA II and explain its mechanism of action. (2 marks)
Describe TWO potential new treatments option for PHA II, including the molecular targets. (2 marks)

A

Established treatment –
thiazides (1 mark)– control hypertension in part by inhibiting reabsorption of sodium (Na+) and chloride (Cl−) ions from the distal convoluted tubules in the kidneys by blocking the thiazide-sensitive Na+-Cl− symporter. (1 mark)

New
• WNKs kinases and the relative kinase inhibitors (1 mark)

or
• SPAK/OSR1 kinases and the relative kinase inhibitors (1 mark)

or
• Inhibitors that disrupt WNKs and SPAK/OSR1 binding (protein-protein interaction)(1 mark)

(1-5) Translational Medical Science (26 decks)

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