Abstract: TH-PO459
Effectiveness of MQ232 in an Orthologous ADPKD Mouse Model
Session Information
- Cystic Kidney Diseases: Clinical Assessment and Therapeutic Directions
October 24, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Cystic
Authors
- Wang, Xiaofang, Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Jiang, Li, Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Hu, Jinghua, Mayo Clinic Minnesota, Rochester, Minnesota, United States
- Gilles, Nicolas, Universite Paris-Saclay, Gif-sur-Yvette, Île-de-France, France
- Torres, Vicente E., Mayo Clinic Minnesota, Rochester, Minnesota, United States
Background
The vasopressin V2 receptor (V2R) inverse agonist Tolvaptan ameliorates the development of polycystic kidney disease (PKD) in orthologous Pkd1 and Pkd2 mouse models and is the only currently approved drug for the treatment of autosomal dominant PKD (ADPKD). However, its benefits are hindered by the dose limiting aquaretic effect and potential hepatotoxicity. Mambaquaretin-1 (MQ1) is a peptide isolated from the venom of the green mamba snake that selectively blocks V2R. Vasopressin binds tightly to the V2R which can simultaneously activate G protein and β-arrestin signaling. Satavaptan, a Tolvaptan-related V2R inverse agonist, inhibits Gαs signaling and cAMP production while activating β-arrestin signaling. In contrast, MQ1 inhibits both V2R activated pathways.
Methods
To confirm the efficacy of MQ1 in an orthologous Pkd1 mouse model and its relative potency compared to tolvaptan, we have treated male Pkd1RC/RC mice with MQ232 (an optimized modification of MQ1), 4 nanomoles/kg/hr via osmotic minipump, or with tolvaptan, 0.2% in powdered food and vehicle via osmotic minipump, along with control mice, from 4 to 16 weeks of age. Osmotic minipumps were replaced every 4 weeks.
Results
MRI kidney volumes at baseline were the same. Tolvaptan and MQ232 reduced kidney and cyst volumes and cAMP (Table 1). MQ lowered plasma urea. Both reduced the kidney tissue levels of p-Thr202/Tyr204 ERK1/2, p-Ser235/236 S6, p-Ser473 Akt, p-Thr308 Akt, and p-Ser9 GSK3β, more markedly in the MQ232 treated mice (Figure 1).
Conclusion
MQ232 ameliorates PKD in an ADPKD orthologous mouse model and is at least as effective as tolvaptan. Studies to further characterize the dose response effectiveness of MQ232 are in progress.
Table 1
| Control (n=10) | Tolvaptan (n=10) | MQ232 (n=10) | |
| Body wt (g) | 30.1±1.4 | 29.4±1.5 | 29.0±1.4 |
| Total Kid wt (g) | 0.81±0.20 | 0.65±0.06* | 0.60±0.11† |
| Kidney wt (%BW) | 2.71±0.67 | 2.22±0.21* | 2.05±0.33* |
| Kid Cyst Vol (μl) | 214.1±99.3 | 139.7±41.6* | 132.6±57.1* |
| Renal cAMP (pmol/mg protein) | 16.1±7.18 | 10.8±1.7* | 8.5±2.3† |
| Plasma Urea (mg/dl) | 52.81±8.4 | 57.5±4.2 | 45.6±5.4* |
| 24 hrs urine (ml) | 1.05±0.35 | 5.24±1.98‡ | 4.90±0.92‡ |
| End TKV (μl) | 1059±234 | 872±112* | 863±122* |
| ttest p value vs control: *<0.05; † <0.01; ‡ <0.001 | |||
Figure 1
Funding
- Other U.S. Government Support