Trigger 3 - WNK-SPAK signalling in Gordon's hypertension syndrome Flashcards
Gordon’s Syndrome, also known as Pseudohypoaldosteronism type II (PHAII), is primarily associated with abnormalities in the ______ pathway.
WNK-SPAK/OSR1-NCC
Provide a brief description of the CUL3-KLHL3 E3 ligase complex and its role in Gordon’s Syndrome.
The CUL3-KLHL3 complex is responsible for ubiquitinating WNK1 and WNK4, leading to their degradation. Mutations in CUL3 or KLHL3 can disrupt this process, resulting in elevated WNK1/4 levels and contributing to the pathogenesis of PHAII.
Thiazide diuretics can be used to treat Gordon’s Syndrome by directly inhibiting the WNK-SPAK/OSR1-NCC pathway. (True/False)
False, that act in the NCC only
What is the primary consequence of mutations in WNK1 and WNK4 in Gordon’s Syndrome?
a) Reduced SPAK/OSR1 activation
b) Elevated SPAK/OSR1 activation
c) Decreased NCC phosphorylation
d) Increased plasma renin levels
b) Elevated SPAK/OSR1 activation
The WNK-SPAK/OSR1-NCC pathway involves the phosphorylation of NCC at specific residues, facilitating NaCl cotransport from the tubule lumen to the ______.
Tubule cells
Elaborate on the clinical manifestations of Gordon’s Syndrome (PHAII).
Gordon’s Syndrome is characterized by hypertension, hyperkalemia, metabolic acidosis, and hyperchloremia. Additionally, patients often exhibit suppressed plasma renin levels and variable serum aldosterone levels.
Thiazide diuretics treat Gordon’s Syndrome by inhibiting the sodium-potassium pump in the kidneys. (True/False)
False
Which of the following is a potential drug target for treating Gordon’s Syndrome?
a) Calcium channel blockers
b) Blocking WNK-SPAK interactions
c) Insulin sensitizers
d) Antihistamines
b) Blocking WNK-SPAK interactions
In Gordon’s Syndrome, CUL3-KLHL3 mutations disrupt the ______ of WNK1 and WNK4.
Ubiquitination
How do thiazide diuretics contribute to the treatment of Gordon’s Syndrome?
Thiazide diuretics compete for the chloride binding site on NCC, promoting sodium and potassium excretion and helping to alleviate hypertension and hyperkalemia in patients with PHAII.
Gordon’s Syndrome is a form of secondary hypertension caused by mutations in genes encoding regulators of renal ______ transport.
Sodium chloride (NaCl)
Explain the role of the WNK-SPAK/OSR1-NCC pathway in the regulation of sodium reabsorption in the kidneys.
The WNK-SPAK/OSR1-NCC pathway regulates sodium chloride (NaCl) cotransport in the distal convoluted tubules of the kidneys. WNK1 and WNK4 kinases phosphorylate and activate SPAK/OSR1, leading to increased phosphorylation of the sodium-chloride cotransporter (NCC). This activation enhances NaCl reabsorption, contributing to blood pressure regulation.
Gordon’s Syndrome is associated with low plasma renin levels. (True/False)
False
Mutations in which of the following genes are associated with Gordon’s Syndrome?
a) ACE
b) AGT
c) CUL3
d) Renin
c) CUL3
The CUL3-KLHL3 E3 ligase complex targets WNK1 and WNK4 for ______, preventing their accumulation.
Ubiquitination
How does Gordon’s Syndrome lead to hyperkalemia, and what are the potential consequences of elevated serum potassium levels?
Gordon’s Syndrome causes hyperkalemia due to increased activity of the WNK-SPAK/OSR1-NCC pathway, impairing potassium excretion. Elevated serum potassium can lead to cardiac arrhythmias and other complications.
The CUL3-KLHL3 E3 ligase complex is responsible for activating WNK1 and WNK4. (True/False)
False
Which of the following is a symptom of Gordon’s Syndrome?
a) Hypokalemia
b) Hypertension
c) Alkalosis
d) Low blood volume
b) Hypertension
Thiazide diuretics exert their effect by inhibiting the ______ cotransporter in the distal convoluted tubules.
Sodium-chloride (NaCl)
Discuss the physiological consequences of impaired WNK-SPAK/OSR1-NCC pathway regulation in Gordon’s Syndrome.
Impaired regulation of the WNK-SPAK/OSR1-NCC pathway in Gordon’s Syndrome results in increased sodium reabsorption, leading to hypertension, hyperkalemia, metabolic acidosis, and altered electrolyte balance.
Thiazide diuretics are often prescribed for the treatment of hypertension, and they work by inhibiting the sodium-chloride cotransporter in the ______.
Distal convoluted tubules
Elaborate on the relationship between WNK kinases and SPAK/OSR1 in the context of sodium reabsorption.
WNK kinases activate SPAK/OSR1, which, in turn, phosphorylates and activates the sodium-chloride cotransporter (NCC) in the kidneys. This activation enhances sodium reabsorption, contributing to blood pressure regulation.
Elevated serum potassium levels in Gordon’s Syndrome can result in hypokalemia. (True/False)
False
In Gordon’s Syndrome, which of the following ions experiences increased reabsorption due to the dysregulation of the WNK-SPAK/OSR1-NCC pathway?
a) Sodium
b) Potassium
c) Calcium
d) Chloride
a) Sodium