Gattone's "Inhibition of renal cyst disease development and progression by a vasopressin V2 receptor antagonist" 2003
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[edit] Abstract
- PKD had no treatment at the time of publishing.
- There are two forms: autosomal recessive PKD (ARPKD) and nephronophthisis (NPH).
- Both have characteristic collecting duct cyst formation.
- They used an animal model of the disease.
- They administered a drug-candidate molecule.
- We already knew that cAMP levels were high in the diseased state and that they contributed to cyst formation through the vasopressin V2 receptor.
- OPC31260 was the drug-candidate they applied.
- OPC31260 binds to vasopresin V2 receptor (VPV2R) as an antagonist to it's activity.
- Upon treatment they saw halting of disease progression or even regression of the disease state.
[edit] Figure 1: Polycystin pathway
- The pathway starts with proteins on the primary follicle that sense extracellular signals.
- These detectors activate proteins that increase intracellular Ca concentrations through the release of Ca fromt he ER and by moving Ca in from extracellular fluid.
- When Ca rises:
- adenylyl cyclase VI is activated which generates cAMP,
- cAMP-dependent PDE
- Therefore cAMP levels rise in the cell.
[edit] Figure 2: Metrics
- They measured levels of cAMP, VPV2R, and aquaporin in diseased and wildtype mice.
- This showed the expected increase in cAMP in diseased state, the decrease in cAMP after intervention, and the steady levels of VPV2R.
- Aquaporin levels were measured because it is positively regulated by cAMP and VPV2R.
[edit] Figure 3: Development and Progression
- They measured things like kidney weight and renal fibrosis volume to show that disease development was decreased upon intervention and also that disease progression was decreased upon intervention.
[edit] Figure 4: Histology
- They show there are fewer and smaller cysts in the treated subjects.
