Gordon's Hypertension Flashcards
What is the BP cutoff for hypertension?
120/80mmHg or below = ideal
140/90mmHg = stage 1/hypertension
160/100mmHg = stage 2/severe hypertension
What are the shared diagnostic features of hypoaldosteronism and Gordon’s hypertensions syndrome?
Hypertension
Hyperkalemia
Hyperchloremia
Metabolic acidosis
What is the function of aldosterone?
Upregulation of Na+/K+ antiporter on the basolateral membrane of principal cells in the DCT. Increases sodium reabsorption and potassium excretion
What are the other main diagnostic features of Gordon’s Hypertension Syndrome?
Low renin
Normal renal function/GFR
High sensitivity to treatment with thiazide diuretics
How is chloride ion homeostasis maintained?
KCC channels responsible for chloride ion efflux
NKCC channels responsible for chloride ion influx. This includes the NCC Na+/Cl- cotransporter in the DCT, and the NKCC1/2 Na+/K+/2Cl- cotransporters in the ascending loop of Henle
What is the function of a kinase?
Transfers a phosphate from ATP to a protein, forming a phospho-protein that has different activity
How are WNK1/4 kinases activated?
By hyperosmotic or hypertonic stress, caused by low intracellular levels of chloride ions
What is the target of WNK1/4 and how does it recognise its target?
Recognises SPAK/OSR1 by the conserved CCT domains
Phosphorylation of SPAK/OSR1 on the T loop
What is the function of SPAK/OSR1 when activated?
SPAK/OSR1 binds to/recognises the NCC and NKCC2 channels using its CCT domain
It phosphorylates
- the Thr60 residue on the N terminus of the NCC channel
- the NKCC2 channel
Leads to increased activity
Greater Na+/Cl-/K+ absorption
Raised BP
How is the activity of WNK1/4 regulated?
The CUL3-KLHL3 E3 ligase complex ubiquitinates it to mark for proteasomal degradation
Describe the process of ubiquitination
- Activation of ubiquitin by E1 (ATP-dependent)
- Transfer of ubiquitin from E1 to the active site of E2
- E2 recruits E3 and the target protein
- E3 catalyses ligation of ubiquitin onto the target protein
What are the components of the CUL3-KLHL3 E3 ligase complex?
Cullin 3 - scaffold protein, joined to KLHL3 and Rbx
Kelch-like 3 - (contains BTB domain that interacts with N terminus of CUL3, and is responsible for recruiting WNK1/4)
E3 ubiquitin ligase, E1 and E2
Rbx (ring box protein 1) - recruits E2
What are the possible mutations that can lead to Gordon’s Hypertension Syndrome?
WNK1 - cannot be ubiquitinated
WNK4 - missense mutation in C terminal non-catalytic domain where KLHL3 would bind, so cannot be ubiquitinated
The BTB domain of KLHL3 - cannot interact with CUL3
CUL3 - cannot ubiquitinate WNK
All lead to gain of function in WNK1/4
Which mutations cause the most severe hypertension phenotype?
KLHL3 or CUL3 - as they regulated both WNKs. If one of the WNK proteins is mutated the other is usually unaffected
What is the mechanism of Gitelman’s Syndrome?
Loss of function in the NCC Na+/Cl- cotransporter
Not enough reabsorption of sodium and chloride
Low BP
What are the current therapeutic options for Gordon’s Hypertension?
Thiazide Diuretics
Loops diuretics
Low sodium and potassium diet
How do thiazide diuretics work and what are the side effects?
Antagonists of the NCC cotransporter
E.g. chlorothiazide
Leads to increased potassium excretion in collecting duct (hypokalemia)
Increased excretion of hydrogen ions (metabolic alkalosis)
Hypercalcaemia
How do loop diuretics work and what are the side effects?
Inhibitor of the NKCC2 cotransporter
E.g. Furosemide
Prevents formation of concentration gradient in the medulla, so less reabsorption of water in the collecting duct
Can also cause hypokalemia
What are the possible future treatments for Gordon’s Hypertension and what are the benefits?
SPAK inhibitors
Prevents phosphorylation of the NCC and NKCC2
Affects all channels rather than just one
Would not cause hypokalemia
Why is chloride ion homeostasis important?
Determines the strength of GABAergic neurotransmission
Structure of KLHL3 and function of each part
BTB domain - binds CUL3
Structure of WNK1/4 and function of each part
Non catalytic domain towards C terminus - where KLHL3 binds
N terminal catalytic domain - phosphorylates SPAK/OSR1
Coiled coil domain (CCD) - recognises/binds SPAK/OSR1
Structure of SPAK/OSR1 and function of each part
T loop kinase domain - where WNK1/4 phosphorylates AND what SPAK/OSR1 uses to phosphorylate NCC and NKCC2
CCT domain - where WNK1/4 binds AND what SPAK/OSR1 uses to bind NCC and NKCC2
How does hypoaldosteronism lead to
- Hyperkalemia
- Hyperchloremia
- Metabolic acidosis
- Reduced Na+/K+ ATPase activity means reduced K+ excretion
- Increased chloride reabsorption in the collecting duct
- Increased chloride reabsorption leads to hyperchloremic acidosis
How does Gordon’s hypertensions syndrome lead to
- Hyperkalemia
- Hyperchloremia
- Metabolic acidosis
- Increased K+ reabsorption by NKCC
- Increased Cl- NCC and NKCC
- Reduced H+ excretion
