Flashcards in Renal Diseases Deck (19)
What are the symptoms of Liddle's syndrome?
Na+ retention, fluid retention, hypertension, hypokalaemia, metabolic alkalosis, low renin and aldosterone levels
What causes Liddle's syndrome?
An autosomal dominant, gain of function mutation of ENaC in principal cells
What is the structure of the ENaC protein?
Alpha, beta and gamma subunits - all needed for normal function
Where is the Liddle's mutation in the ENaC protein?
In the COOH tail of beta or gamma subunits
Deletion of the proline rich motif
What is the normal function of the proline rich motif in ENaC?
It allows the ubiquitination of ENaC which is important to allow the endocytosis of ENaC from the membrane
What happens as a result of this loss of the proline rich motif in Liddle's syndrome?
Endocytosis can't occur at the same rate and therefore Na+ reabsorption is increased
How do you experimentally show the effect of Liddle's syndrome?
Over express in xenopus oocytes, traces will show there are roughly double the amount of Na channels in mutants compared with wild-type
How do the symptoms seen in patients with Liddle's syndrome arise?
Excessive Na+ movement into the cell also leads to excessive H2O - this causes hypertension
More Na+ influx means more K+ secretion - hypokalaemia
-ve membrane potential drives H+ secretion - metabolic alkalosis
How do Liddle's patients and normal individuals respond differently to an increase in blood pressure?
Increased BP = decreased renin and aldosterone = loss of ENaC from apical membrane of principal cells = decreased Na+
Hypertension = decreased renin and aldosterone = ENaC cannot be removed = no reduction in Na+ reabsorption =hypertension persists
How is Liddle's syndrome treated?
Spironolactone (MR receptor agonist) shows hypertension is nothing to do with aldosterone and it is to do with ENaC
What are the symptoms of diabetes insipidus?
Polyuria with compensatory polydipsia
What are the four types of diabetes insipidus?
Primary polydipsia (suppressed AVP production from excessive H2O)
Gestational (decreased AVP levels, metabolised by placental enzymes)
What causes central diabetes insipidus?
Acquired - infection, head trauma, surgery
Congenital - 67 mutations in the AVP gene, make a version of vasopression that can't be trafficked
What causes nephrogenic diabetes insipidus?
Acquired - lithium (bipolar medication), some antibiotics and antifungals, hypokalaemia (reduction in AQP2), hypercalciuria, acute and chronic renal failures
Congenital - mutations in AVPR2 (X linked) or AQP2 gene. AQP2 impacts trafficking (dominant) or function (recessive) of protein
What are symptoms of congenital nephrogenic diabetes insipidus in infants?
Hypernatrimic dehydration, poor feeding, skin dryness, depressed anterior fontanelle
What are treatments of central diabetes insipidus?
Desmopressin - activates vasopressin receptors and increase urine osmolality
Why is nephrogenic diabetes insipidus difficult to treat?
Patients can't respond to vasopressin
What are some treatments of nephrogenic diabetes inspidius and how do they work?
Cell permeable antagonists - attach to misfolded vasopressin receptor to correct it, AQP attaches to the membrane
Cell permeable receptor agonists - stimulate misfolded vasopressin receptor and allow downstream signalling
Cell permeable agonists - binds to misfolded receptor, corrects it and stimulates it to allow downstream activation
Compounds that bypass V2R signalling - target prostaglandin receptors, cAMP, insertion of AQP2 channels