Lecture 4 Flashcards
What is Liddle’s syndrome and when was it described?
Was described in 1963. Is an autosomal dominant disease due to a gain of function mutation in ENac. Water and salt retention resulting in metabolic alkalosis, hypertension, down regulation of renin and aldosterone (as they cause vasoconstriction), hypokalaemia (secondary effect).
How is ENac mutated in Liddle’s syndrome?
Has three subunits= alpha, beta and gamma. Is mutated on the COOH end of beta/gamma which is a proline rich domain that interacts with Led42 to be ubiquitinated and degraded. Usually regulated by renin and aldosterone but can’t be endocytosed so there is more on the apical membrane
How can ENaC activity be measured and why is a xenopus oocyte used?
They are 2mm and robust. Inject mRNA of alpha, beta and gamma subunit- allows rat ENaC to be overexpressed. Mutants are open 6/7 times whereas WT are open 2/3 times. Measure currents= mutant is doubled meaning there is more ENaC on the membrane.
How are the secondary effects of Liddle’s syndrome caused?
1) Hypertension= decrease in renin aldosterone causes endocytosis of ENaC but because it can’t be removed, hypertension persists
2) Hypokalaemia= due to excess use of sodium potassium pump
3) Metabolic alkalosis= Increase in sodium uptake causes increase in charge (decrease in membrane potential) therefore more action from the potassium proton exchanger and proton pump to secrete protons into urine
What are the effects of amiloride on Liddle’s syndrome?
Is a ENaC blocker- in child patients, their BP is the same as an adult’s. With amiloride it drops from 121 to 98. Also causes decrease loss in K+ and drop in pH back to normal levels, but the Na+ concentration remains the same as water follows it.
Why was spironolactone used to test amiloride function?
Used as a control as it is an MR receptor antagonist to prove that it is in fact ENaC that causes hypertension and not the aldosterone pathway
What is the cause of the symptoms of diabetes insipidus?
1) AVP binds to vasopressin2 R
2) conversion of ATP to cAMP
3) cAMP activates PKA
4) PKA phosphorylates AQ2 vesicles which get trafficked to membrane which allows water reabsorption (leave the cell through AQP3 and 4 which are constitutively active)
What are the symptoms and statistics of diabetes insipidus?
Problems with AP2-vasopressin system. Effects 1:25,000-30,000 individuals. Causes polyuria and polydipsia- causes dehydration
What are the types of diabetes insipidus and how do they arise?
1) Central= failure of hypothalamus production of vasopressin- can be congenital or acquired
2) Primary Polydipsia= Excess water drinking which results in low vasopressin= increase in urine flow rate
3) Gestational= most common in pregnant women as placenta secretes enzyme that breaks down vasopressin
4) Nephrogenic= can produce AVP but can’t react to it
What percentage of DI is congenital?
less than 10%
What are the causes of central DI?
Acquired= head trauma, surgery, injury, infection- impact on central structures to detect changes in osmolality or release AVP congenital= neurohypophyseal DI= caused by 67 mutations found in the vasopressin gene- prevents it from being trafficked to the posterior pituitary or secrete a type that isn't activated.
What are the causes of nephrogenic DI?
Acquired= fungal treatments, anti-neoplatics (chemo therapy), lithium from bipolar treatments. Hypokalaemia and hypercalciuria cause a down regulation of AQ2 on the membrane Congenital= X linked mutation in AVPR2 or AQ2 which prevents trafficking (dominant) or function (recessive). Symptoms appear in infants- health visiter looks for hypernatremic dehydration, dry skin, don't feed properly, depressed anterior fontanel= depression of skull and bones don't fuse properly due to less fluid in the skull- can cause death or dehydration
What are the treatments for central DI?
desmopressin (sounds like vasopressin)- a nasal spray that activates vasopressin and needs to be taken at the correct times- increases urine osmolality
How is nephrogenic DI treated?
1) Cell permeable antagonists= target misfolded VR2 to the membrane and correct its folding- AVP replaces it to activate the R
2) Cell permeable agonists= Correct the folding of VR2 and traffic it and then activate it
3) Cell permeable receptor agonists- activate the misfolded R inside the cell to activate signalling
4) Compounds that bypass signalling= PDE5 antagonist (prevent cGMP breakdown) PDE4 inhibitor (prevent cAMP breakdown), Hsp90 inhibitor (allows trafficking of misfolded AQ2 to the membane), prostaglandin agonist (stimulate AQ2 production) and statins (prevent internalisation of AQ2)
