Gordens Hypertension Syndrome

Question 1

What is Hypertension?

Answer 1

Is the sustained elevation of blood pressure

Question 2

What is systolic blood pressure?

Answer 2

> 140 mm Hg

Systolic pressure> cuff pressure

Question 3

What is diastolic blood pressure?

Answer 3

> 90 mm Hg

Diastolic pressure> cuff pressure.]

Question 4

What is normal blood flow?

Answer 4

No occlusion of blood flow

Question 5

What is Blood Occlusion?

Answer 5

cuff pressure blocks blood flow

Question 6

What is the normal blood pressure?

Answer 6

120/80

Question 7

What is the blood pressure for pre-hypertension?

Answer 7

120-139/80-88

Question 8

What is the blood pressure for stage 1 hypertension?

Answer 8

140-159/90-99

Question 9

What is the blood pressure for stage 2 hypertension?

Answer 9

> 160/100

Question 10

From what blood pressure does cardiovascular disease risk start to double with each increment of 20/10mmHg?

Answer 10

115/75

Question 11

What are the environmental risk factors which contribute to hypertension?

Answer 11

Smoking, bad diet and stress.

Question 12

What are the genetic risk factors which contribute to hypertension?

Answer 12

Mitochondrial genome 
- signalling 
- energy transduction 
- cell death 
Nuclear genome 
- arterial factors 
- kidney and RAAS - mutations 
- metabolic and local hormonal factors 
-CNS

Question 13

What is Gordons Syndrome?

Answer 13

Rare familial form of hypertension; monogenic; fully penetrant- sporadic cases have been reported.
Alternative names - Pseudohypoalsteronsim type II
Familial H& H

Question 14

What are the features of Gordons syndrome?

Answer 14

Hypertenison
Hyperalkalaemia
Normal renal function
Very sensitive to thiazide diuretics.

Question 15

How is hypertenision affected in Gordons Syndrome?

Answer 15

Low-renin type - salt dependent
- Aldosterone levels low for degree of hyperkalaemia.
Alternate names
FHHt + PHA2

Question 16

How is hyperkalaemia affected in Gordons Syndrome?

Answer 16

High serum potassium,

• May be severe (>8mmol/l)
• Metabolic acidosis/ hyperchloraemia(Cl-)
• Muscle weakness

Question 17

What is the treatment goal in Gordons Syndrome?

Answer 17

Is to reduce the overall cardiovascular risk factors and control BP by the least intrusive means possible.
BP<140/90
In patients with diabetes or renal disease the goal is <130/80

Question 18

What are the complications of hypertension?

Answer 18

Target organ diseases

can occur in the heart brain, kidney and eyes.

Question 19

What can causes kidney diseases?

Answer 19

High blood pressure

Question 20

How does the kidney control salt levels?

Answer 20

The Sodium chloride co-transporter
Sodium potassium chloride cotransporter.
There activity, defines salt concentration in urine,
Affecting the blood volume and arterial pressure,
Could be inhibited by loop or thiazide-type diuretics,

Question 21

How much of the blood pumped to the heart is filtered?

Answer 21

20%

Question 22

What does the Sodium chlorine transporter do?

NCC -

Answer 22

Transports sodium and chlorine into the blood. which also maintains ion homeostasis in the blood.
NCC - transmembrane protein.

Question 23

What happens at the N-terminus of the NCC?

Answer 23

Phosphorylated by SPAK/OSR1, which binds to the RFX1 domain

Question 24

What is TAL?

Answer 24

Thick accendini loop

Question 25

Where is the NKCC2? and what does it do?

Answer 25

In the Thick ascending loops. | It extracts Sodium potassium and chlorine from the urine to be reabsorbed into the blood.

Question 26

Analysis of NCC phosphorylation in the DCT cells

Answer 26

Culture the cells in dishes and treat it with hypotonic low Cl-, The cells are phosphorylated, then in osmotic stress

Question 27

What would the radio active sodium uptake assay?

Answer 27

To measure the activity

Question 28

What does Gordons Syndrome entail?

Answer 28

Severe hypertension High serum levels Increased Na reabsorption Sensitivity to thiazide diuretics, antagonists of the Na-Cl co-transporter (NCC).

Question 29

What has sequence similarity with the MEKK-like kinases?

Answer 29

The kinase domain of WNK

Question 30

How does WNK 1/4 phosphorylation and activates SPAK and OSR1?

Answer 30

Activation is mediated by T-loop phosphorylation

Question 31

SPAK and OSR1 are 68% identical, what does this effect?

Answer 31

Possess a highly similar kinase catalytic domain

Question 32

what does the CC terminal domain on the SPAK/OSR1 bind too?

Answer 32

The RFQV motif on the NKCC2, and the RFTI motif on the NCC, Leucine 502 is important for the binding, and is very conserved.

Question 33

How does WNK1 signalling pathway work?

Answer 33

1. Osmotic stress activates WNK1 by phosphorylation, which phosphorylated SPAK/OSR1, on the T-loop. 2. Which regulates the ion channels through phosphorylation NKCC1 NKCC2 NCC

Question 34

Ubiquitination System

Answer 34

1. E1 Activates ubiquitin at the C-terminus through adenylation 2. And transfers it to the E2 (Ubiquitin-conjugating enzyme) by transthiolation 3. E2 and E3 come together forming a complex, Called ubiquitin ligase. 4. E3 binds to degron in the protein, E3 ligates the c-terminus carboxyl group of the ubiquitin to a lysine group on the protein more are added, which can then be recognised by the proteasome.

Question 35

What is the Proteasome?

Answer 35

Compartmentalised protease, which active sites are sequestered (Inaccessible without admission into its proteolytic chamber)

Question 36

How does the proteasome work?

Answer 36

1. Ubiquitin receptor holds the protein in place. 2. Ubiquitin hydrolase (cleaves Ubiquitin from substrate proteins. 3. AAA proteins form a hexametric protein unfoldase, it requires ATP, protein is unfolded, Nucleophile attacks bonds in aa.

Question 37

What mutations cause Gordons Syndrome?

Answer 37

KLHL3 and CUL3

Question 38

A patient has high blood pressure and high potassium levels what disease could they have?

Answer 38

Gordons Syndrome

Question 39

A patient with low blood pressure and low serum levels, are likely to have what disease?

Answer 39

Gitelman

Question 40

What affect does thiazide diuretic have on the body?

Answer 40

Increase renal excretion of Sodium, Potassium and Hydrogen ions (causing metabolic alkalosis) Decreases renal excretion of calcium

Question 41

What are the treatments of Gordons trying to do?

Answer 41

Decrease the phosphorylation of NCC