L4 - Renal Diseases Flashcards
What kind of inheritance is Liddle’s syndrome?
Autosomal dominant
Gain of function mutation in ENaC
Na channel function enhanced
What are the symptoms of Liddle’s syndrome?
Na+ and fluid retention Hypertension Hypokalaemia Metabolic alkalosis Low renin and aldosterone levels
How does the body try and compensate for the hypertension?
Low renin and aldosterone levels
What are the subunits of ENaC?
Alpha, beta, gamma subunits 1:1:1
Where is the Liddle’s mutation found in ENaC?
Found in COOH tail of beta or gamma subunits
Deletion of proline rich motifs
What is the importance of proline rich motifs?
Important endocytosis
Allows ENaC to interact with a ubiquitinate ligase so it can be removed from membrane
If motif deleted endocytosis rate slowed
What causes hypertension and hypokalaemia in ENaC mutant?
In mutant more channels open in principal cell as they cannot be removed by endocytosis
- Excessive Na and water uptake – hypertension
- More Na uptake means more K secretion – hypokalaemia
What causes metabolic alkalosis in ENaC mutant?
In the alpha intercalated cell high Na reabsorption from tubular fluid leaves a negative membrane potential
Leads to an excess of H+ secretion
Creates a transepithelial potential
In a normal individual what sequence of events happens after a rise in BP?
Decrease in renin and aldosterone release
Low aldosterone in principal cells
Loss of ENaC from apical membrane of principal cells
Reduction in Na reabsorption
Fall in BP
In a Liddle’s individual what sequence of events happens after a rise in BP?
Hypertension – high BP
Low renin and aldosterone – compensation mechanism
Cannot remove ENaC from apical membrane principal cells
No reduction in Na reabsorption so hypertension persists
High Na reabsorption
What is the main treatment for Liddle’s syndrome?
Amiloride
What is the effect of Amiloride when used as treatment in an infant?
Reverses high BP
Concentration of Na stays constant but total Na content of plasma changes with an expansion of ECF volume
Reverses loss of K
pH decreases due to a reduced loss of H+
What effect does spironolactone have on treatment of Liddles syndrome?
No effect
MR receptor antagonist (target for aldosterone)
What is diabetes insipidus?
Polyuria with compensatory polydipsia - thirst
Dehydration can be a serious issue
What are the inherited conditions of diabetes insipidus?
1 : 25,000-30,000
Problems with AVP – AQP2 system
What is the sequence of events that happens in the principal cells of the collecting duct resulting in water absorption?
Vasopressin receptor 2 binds AVP
Stimulates receptor leading to activation of PKA
Leads to phosphorylation of AQP2 in vesicles underneath apical membrane
Vesicles fuse with membrane and insert new AQP2
Osmotic driving force for water to enter through AQP2 and out through AQP3+4
- AQP3+4 are constitutively active
Rate limiting factor for water reabsorption is AQP2 in apical membrane
What are the 4 types of diabetes insipidus?
Central
Gestational
Nephrogenic
Primary polydipsia
What is central diabetes insipidus?
Impaired AVP production
Acquired or congenital
What is gestational diabetes insipidus?
Decreased AVP levels
Metabolism by placental enzymes
Only seen in pregnant women
What is nephrogenic diabetes insipidus?
Impaired effect of AVP
Acquired or congenital
What is central primary polydipsia diabetes insipidus?
Suppressed AVP production
Excessive H2O intake
What are the causes of central acquired diabetes insipidus?
Infection
- In hypothalamus or posterior pituitary gland
- Inability to respond to changes in osmolarity of plasms or release vasopressin
Head trauma
Surgery
What are the causes of central congenital diabetes insipidus?
67 mutations in AVP gene
Many mutations important for transport of AVP from hypothalamus to posterior pituitary
- Not transported to pituitary glans
- Not released
- Released but not active
As though they are not releasing AVP at all
What are the causes of nephrogenic acquired diabetes insipidus?
More common
Lithium – bipolar affective disorder treatment
- Impacts on ability to reabsorb water
Some antibiotics, antifungals, antineoplastic agents
Hypokalemia and hypercalciuria
- Reduction in AQP2 levels in the kidney
Acute and chronic renal failure
What are the causes of nephrogenic congenital diabetes insipidus?
Mutations in
- AVPR2 gene – x linked
- AQP2 gene – impact trafficking (dominant) or function (recessive) of protein
When do the symptoms of nephrogenic diabetes insipidus occur?
In infants
What are the symptoms of nephrogenic diabetes insipidus?
Hypernatrimic dehydration – low volume and enhanced Na concentration in plasma
Poor feeding
Skin dryness
Depressed anterior fontanel – some components of skull haven’t fused (depression at front)
What are the treatments for central diabetes insipidus?
Desmopressin
Given through a nasal spray
It activates vasopressin receptors
What are the 4 different treatments for nephrogenic diabetes insipidus?
Cell permeable antagonists
Cell permeable agonists
Compounds that bypass vasopressin 2 receptor signalling
Compounds that can target different parts of pathways downstream of vasopressin receptor
How can cell permeable antagonists be used to treat diabetes insipidus?
1st type
- Target misfolded vasopressin 2 receptor to the membrane
- Then replaced with AVP
2nd type
- Cross the membrane and enter the cell
- Activates misfolded vasopressin 2 receptor signalling – PKA activation
How can cell permeable agonists be used to treat diabetes insipidus?
Aid correct folding and trafficking
Then activates vasopressin 2 receptor signalling
How can compounds that bypass vasopressin 2 receptor signalling be used to treat diabetes insipidus?
Target directly downstream – bypass the mutation
Target prostaglandin receptor
- Activation of cAMP
- Insertion of AQP2 into membrane
What are the 5 compounds that target different parts of the pathway downstream of vasopressin receptors?
Prostaglandin receptor agonists Stimulating cGMP levels Stimulating cAMP levels Statins Heat shock protein 90 inhibitors
How can prostaglandin receptor agonists be used to treat diabetes insipidus?
Induce AQP2 expression and membrane abundance
How can cGMP level be used to treat diabetes insipidus?
PDE5 inhibitors – prevent breakdown cGMP
Stimulates insertion of AQP2
How can cAMP levels be used to treat diabetes insipidus?
PDE4 inhibitors – prevent breakdown cAMP
Stimulates insertion of AQP2
How can statins be used to treat diabetes insipidus?
Prevent internalisation AQP2
How can heat shock protein 90 inhibitors be used to treat diabetes insipidus?
Allows misfolded AQP2 to reach the membrane
