Kidney Flashcards
what is Liddle’s syndrome?
a rare genetic disorder of Na balance
What is Liddle’s syndrome?
described in 1963, it is an inherited autosomal dominant disease. patients get Na retention i.e. they dont excrete Na in the urine that they normally would have done. they retain fluid due to retaining this Na and so therefore, they have too much fluid that leads to hypertension.
why do patients with Liddle’s have a problem with hyperkalemia and metabolic alkalosis?
this links to reabsorption of too much Na in the late distal tubule and the collecting duct so they are secreting more K and H ions into their urine and so they have low plasmid K and have an alkalosis
what is the difference between Liddle’s patients and normal patients?
the way that their body reacts is that it recognises that it is reabsorbing too much Na and so if you get an expansion of the EC fluid volume, this downregulates production of renin and aldosterone because this is what controls how much Na is reabsorbed in the late distal tubule and in the collecting duct
this low renin and aldosterone levels in the patients is the body’s way to try and compensate
they drop renin and aldosterone levels down and in a normal individual, this would educe Na reabsorption in that part of the nephron (in the collecting duct). this doesn’t work in Liddle’s patient because they have this defect in these cells and so they are not able to respond to the aldosterone
what subunits make up ENAC?
ENAC is made of 4 subunits - 2 alpha, 1 beta and 1 gamma
each of the subunits are made up of 2 TM spanning domains, an EC loop and an IC amino carboxy termini
this is the same for alpha, beta and gamma
what subunit of ENAC is sufficient for its function? how is it linked to Liddle’s
alpha by itself is sufficient to form functional channels but this function is not normal. you need all 3 subunits to have normal functional epithelial Na channels in the apical membrane of the principle cells and the collecting duct
the part relevant to Liddle’s syndrome is the proline rich part of the carboxy terminus of all 3 units
mutations in this area in the beta and gamma subunits that are traditionally associated with incidents of Liddle’s syndrome
this particular proline region plays an important role in the cells ability to ubiquitinate the ENAC proteins which means that it targets the protein for endocytosis
mutations in what subunits of ENAC are normally associated with Liddle’s? why is this?
in the beta and gamma subunits.
this is because this specific proline region plays an important role in the cells ability to ubiquitinate the ENAC proteins so it targets the protein for endocytosis
how can the mutation of a proline region affect ENAC?
there will be a problem with how ENAC channels are removed from the membrane. anything that disrupts this sequence in the subunits will disrupt ubiquitination and endocytosis of ENAC and so more are on the membrane so there is more Na and water moving through
