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Translational Medical Sciences > Gordon's Hypertension Syndrome > Flashcards

Gordon's Hypertension Syndrome Flashcards

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USMLE® Step 1 flashcards
1
Q

Define hypertension

A

sustained elevated BP levels (140/90 mmHg)

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2
Q

What is prehypertension

A

BP levels above optimum levels (>=120/80 mm Hg)

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3
Q

What are BP levels for stage 1 and stage 2 hypertension respectively

A

Stage 1: >= 140/90 mmHg

Stage 2: >= 160/99-100 mm Hg

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4
Q

What are the risk factors for primary hypertension

A 
Environmental factors
- Stress
- Diet
- Smoking
Genetic factors
- Mitochondrial genome
  - energy transduction
  - cell death
  - signalling pathways
- Nuclear genome
  - arterial factors
  - kidney and RAAS
  - CNS
  - metabolic and local hormonal factors
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5
Q

Illustrate the main features of gordon’s hypertension syndrome

A
  • PHAIIA, FHHt
  • rare
  • monogenic
  • 100% penetrance
  • Hyperkalemia
    • increased potassium levels (>8mmol/l)
    • metabolic acidosis (hyperchloremia)
    • muscle weakness, maybe even periodic paralysis
  • Hypertension
    • of the low renin type (salt dependent)
    • low aldosterone levels
  • Normal renal function
  • Very sensitive to thiazide diuretics
  • short stature
  • severe hypertension by third decade of life
  • dental abnormalities
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6
Q

What are the treatment goals for PHAIIA?

A
  • reduce overall cardiovascular risk factors
  • reduce BP by least intrusive methods
  • BP <140/90
  • for diabetics and people with kidney disease, aim is <130/80
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7
Q

Describe hyperkalemia and associated problems

A

increased potassium levels (>8mmol/l)

  • metabolic acidosis (hyperchloremia)
  • muscle weakness, maybe even periodic paralysis
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8
Q

What are the common target organs of hypertension

A
  • heart
  • kidney
  • brain
  • eyes
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9
Q

What is the relationship between kidneys and blood pressure

A
  • unhealthy kidneys can affect BP and high BP can affect kidneys
  • if you have kidney disease, you are not highly likely to get kidney failure, but more likely to have CV disease or stroke
  • imp to maintain BP when you have kidney disease
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10
Q

In Gordon’s hypertension syndrome, what regulates the WNK1/4-NCC signalling pathway?

A

CUL3/KLHL3

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11
Q

How does a kidney control salt levels in the body

A
  • Kidney receives 1/5th of blood from the heart
  • Blood received gets filtered by nephrons in the glomerulus
  • about 90% of salt gets reabsorbed
  • DCT also plays an important role as it is the reabsorbs 5-10% of all sodium
  • DCT also controls homeostasis of Mg and Ca
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12
Q

What is the role of the kidney nephron?

A
  • in the glomerulus
  • filters 1/5th of blood from heart
  • salt reabsorption
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13
Q

What is the NCC and NKCCs

A
  • NCC is the sodium-chloride sympoter present in the apical membrane of the DCT
  • Symport Na and Cl in electroneutral manner into cell for 5-10% of NaCl reabsorption
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14
Q

Describe the activity of Sodium-chloride symporters in the convoluted tubules

A
  • describe the salt concentration in urine
  • regulate blood volume and arterial pressure
  • can be inhibited by loop or thiazide dieuretics
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15
Q

Describe the WNK-SPAK-NCC signalling pathway in the kidney

A
  • NCC is found in the apical membrane of the DCT
  • NCC is regulated by the WNK-SPAK signalling cascade
  • Activated WNK kinase binds to SPAK and phosphorylates it at Thr243
  • Active phospho-SPAK binds to NCC and phosphorylates it at Thr60
  • Activated pNCC increases intrinsic activity and increases influx of Na
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16
Q

How are thiazides used to treat hypertension

A
  • thiazides block NCC to diuresis via salt wasting
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17
Q

What are NCC and NKCC associated with

A

Chlorine influx

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18
Q

What is KCC associated with

A

Chlorine efflux

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19
Q

What are CCCs and why are they important

A
  • Cation Chloride co-transporters
  • Imp for mediated of cellular chloride homeostasis
  • chloride effluxers (pump chloride out of cell)
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20
Q

What is a protein kinase

A
  • A protein kinase is a kinase enzyme that modifies proteins by adding phosphate groups to it (phosphorylation)
  • Phosphorylation modifies substrates (target enzyme) by changing protein activity, cellular location or association with other proteins
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21
Q

Describe the human kinome

A
  • 2% of all human genes
  • up to 30% of all proteins are regulated by kinases
  • regulate majority of pathways involved in signal transduction
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22
Q

What is Gordon’s hypertension syndrome caused by

A

mutations in WNK1 and WNK4 (WNK kinases)

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23
Q

What is a thiazide

A
  • Thiazide diuretics are NCC antagonists that produce diuresis through salt wasting
24
Q

What are WNK kinases

A
  • with no lysine kinases
  • large proteins
  • 30% similarity with MEKK family of kinases
  • catalytic lysine is at glycine rich B-strand 2 anchors and binds ATP
25
Q

What is unique about the crystal structure of WNK1

A
  • kinase domain is in ribbon format
  • enlargement of active site
  • K233 catalytic lysine on strand 2 vs normal lysine C250 on strand 3
26
Q

Which WNK is found in the kidney and has neuronal isoforms as well

A

WNK1

27
Q

What are some defining features of neuronal WNK1

A
  • additional exons have been reported
  • lacks exons 11-12 in brain and spinal cord, lacks exon 11 in dorsal root gangalia
  • doesn’t have non-catalytic residues on N-terminal
28
Q

What phosphorylates SPAK/OSR1

A

Wnk1/4

29
Q

What is SPAK/OSR1 activation mediated by

A

T-loop phosphorylation

30
Q

What are the similarities between SPAK/OSR1

A
  • 68% identical in sequence

- highly similar (90%) catalytic kinase domains

31
Q

Outline the basic functioning of the WNK-SPAK/OSR1 pathway

A
  • Hyperosmotic/hypotonic stress phosphorylates WNK1
  • Active WNK1 kinase phosphorylates SPAK/OSR1
  • Activated SPAK/OSR1 phosphorylates conserved T-residues in N terminal of NCC and NKCC
  • NCC and NKCC intrinsic activity is increased and there is Na influx
32
Q

Describe the relationship between SPAK and WNK1

A

SPAK associates with WNK1 and SPAK-CCT mutation disrupts the interaction

33
Q

Does WNK phosphorylate NCC directly

A

No, WNK phosphorylates and activates SPAK which in turn phosphorylates NCC

34
Q

Describe the WNK1 putative signalling pathway with a diagram

A
  • Osmotic stress phosphorylates WNK1
  • pWNK1 phosphorylates SPAK/OSR1
  • activated SPAK/OSR1 phosphorylates ion cotransporters NKCC1, NCC, NKCC2
  • pNKCC1= influx of Na, K, 2Cl ions
  • pNCC= influx of Na and Cl ions
  • pNKCC2= influx of Na, K, 2Cl ions
35
Q

What mutations have been associated with GHS

A
  • mutations in WNK1/4

- mutations in KLHL3 and CUL3

36
Q

What is ubiquitination

A

Ubiquitination is a post-translational modification in which a ubiquitin protein is attached to a substrate protein

37
Q

Describe the ubiquitination process via a diagram

A
  1. Activation by ubiquitin activating enzyme (E1), 2 step process, ATP dependent
  2. Conjugation by ubiquitin conjugating enzyme (E2), catalyses transfer of Ub from E1 to active site cysteine on E2 via trans(thio)esterification reaction
  3. Ligation by ubiquitin ligases (E3) which catalyse the final step of the cascade
38
Q

What is a substrate for CUL3-KLHL3

A

WNK1 (in vitro)

39
Q

What mutation in CUL3 causes GHS

A

deletion of exon 9

40
Q

How does a CUL3 mutation cause GHS

A
  • a mutation of CUL3 doesn’t allow WNK1/4 to be ubiquitinated
41
Q

What three mutations are mainly responsible for GHS

A
  • Affect the binding of WNK4 to KLHL3-Cul3 complex
  • mutations in acidic domain of WNK4
  • mutations in Kelch domains of KLHL3
  • Exhibits lower E3 ligase activity in combination with KLHL3
  • deletion of exon 9 in Cul3
42
Q

What is the overall effect of mutations in GHS

A
  • decreased ubiquitination
  • increased levels of WNK4 in cells
  • other WNKs expressed at low levels can also be increased
43
Q

What is the molecular pathogenesis of GHS

A
  • Decreased degradation of WNK4 due to mutations in WNK4 (acidic domain), KLHL3 (R528+/-, Kelch domain), Cul3 (exhibits lower E3 ligase activity w KLHL3, exon9 deletion)
  • Increased WNK4 levels
  • Increased phosphorylation of SPAK/OSR1 and hence NCC
  • increased intrinsic NCC activity, increased influx of Na+, CL-
44
Q

What are the treatment options for GHS

A
  • low salt diet

- thiazide dieuretics (NCC inhibitors)

45
Q

What is the pathogenesis of Gitten’s syndrome

A
  • Low BP
  • Low serum K+
  • Loss of function of NCC
  • Point mutations and C-terminal truncations in NCC gene
46
Q

What is the pathogenesis of GHS

A
  • High BP
  • High serum K+
  • Gain of function of NCC
  • Genomic sequence of NCC gene is normal
47
Q

Give two examples of diuretics

A
  • Diuril

- Microzide

48
Q

What is the overall effect of diuretics

A
  • Inhibit NCCS to
    • Increase renal excretion of Na, K, H+ (causing metabolic alkalosis)
    • Decrease renal excretion of Ca
49
Q

How do thiazides work

A
  • Inhibit uptake of Na by NCC on lumen
  • This in turn leads to a decrease in intracellular Na
  • in turn results in lowering of intracellular Ca as Ca leaves the cell via basolateral side as Na comes in
  • Ca diffuses in via Ca ion channels on lumen side
  • Inhibition of Na transport in this part leads to greater delivery of Na to the collecting duct
  • In collecting duct, increased Na influx leads to K efflux (cauding hypokalemia)
50
Q

What are the downstream effects of thiazides

A
  • Lowering of intracellular Na facilitates Ca reabsorption
  • Inhibiting Na transport leads to greater delivery of Na in the collecting duct
  • In collecting duct, Na influx leads to K efflux (which causes hypokalemia)
51
Q

What is the result of increased renal excretion of hydrogen ions caused by thiazide diuretics?

A

Metabolic alkalosis

52
Q

How do you diagnose Gordon’s syndrome?

A

Genetic testing of the proband to identify a heterozygous pathogenic variant in CUL3, WNK1, WNK4 or KLHL3 or a biallelic pathogenic variant in KLHL3

53
Q

How is ROMK involved in hyperkalemia?

A
  • Channels in the kidney
  • Regulated to adjust renal potassium excretion and maintain potassium balance
  • Expression remains unaltered in mouse models of Gordon’s syndrome
54
Q

Where is ROMK predominantly expressed?

A

TAL and cortical collecting duct of nephrons

55
Q

Suggest an alternative therapy for GHS

A
  • an inhibitor which binds to the CCT domain of SPAK/OSR1 and prevents WNK-SPAK binding

Translational Medical Sciences (8 decks)

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