Gattone's "Inhibition of renal cyst disease development and progression by a vasopressin V2 receptor antagonist" 2003

From Biol557

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Current revision as of 13:02, 27 April 2010

Contents 1 Abstract 2 Figure 1: Polycystin pathway 3 Figure 2: Metrics 4 Figure 3: Development and Progression 5 Figure 4: Histology

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.

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.

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.

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.

Figure 4: Histology

• They show there are fewer and smaller cysts in the treated subjects.