Abstract: FR-PO722
Pioglitazone and Tolvaptan in a Mouse Model of Autosomal Dominant Polycystic Kidney Disease (ADPKD)
Session Information
- Cystic Kidney Diseases: Clinical/Translational
November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1001 Genetic Diseases of the Kidneys: Cystic
Authors
- Kanhai, Anish A., Leiden University Medical Center, Leiden, Netherlands
- Bange, Hester, OcellO, Leiden, Netherlands
- Price, Leo Sebastian, OcellO, Leiden, Netherlands
- Peters, Dorien J.M., Leiden University Medical Center, Leiden, Netherlands
- Leonhard, Wouter N., Leiden University Medical Center, Leiden, Netherlands
Background
ADPKD is characterized by fluid-filled cyst formation and mainly caused by mutations in the PKD1 gene. Currently, the only treatment option for ADPKD is the vasopressin V2 receptor antagonist tolvaptan (TVP). However, due to unfavourable side effects, the drug is not well tolerated by all patients, leaving a need for alternative approaches. We hypothesized that a combination treatment can result in a better therapy, as the complex intracellular signalling involved in ADPKD is then targeted from various angles simultaneously. We conducted a preclinical study in an adult onset ADPKD model to investigate the effects of a combination treatment of TVP and pioglitazone (PIO), a peroxisome proliferator-activated receptor gamma (PPARγ) agonist. This drug slows disease progression in two PKD rat models (Blazer-Yost et al., PPAR Res 2010 & Flaig et al., J Trans Int Med 2016), and is now tested in a clinical trial for ADPKD.
Methods
In vitro: PIO was tested in a 3D cyst model for PKD (mIMCD3-Pkd1-/- cells) to evaluate its efficacy on reducing cyst swelling. In vivo: An inducible adult onset model for ADPKD (P18KspPkd1del mice) was used. Following Pkd1 inactivation by tamoxifen on postnatal day 18/19, mice (n = 20 males per group) were fed with food pellets containing 0.1% TVP and/or 0.1875% PIO. Mice were treated until 50% of the untreated group had renal failure (blood urea levels > 20 mmol/l).
Results
PIO was effective in reducing cyst swelling in vitro. TVP was able to improve renal survival in mice (86% vs. 41% in the untreated group, p<0.01) and reduced 2KW/BW% by 2-fold (p<0.001). Plasma adiponectin, a surrogate drug marker for PIO treatment, was higher in PIO-treated mice, to a similar extent as in humans after PIO treatment. However, PIO had no effect on renal survival and on downstream PPARγ signalling in the kidney. Also, Pparg gene and PPARγ protein expression was very low in wildtype, cystic and PIO-treated kidneys.
Conclusion
TVP improved renal survival and reduced cyst growth, confirming our model’s relevance to ADPKD. Despite in vitro efficacy and using a clinically relevant dose, PIO had no therapeutic benefit in vivo, possibly due to low expression of PPARγ in mouse kidneys. Further research on the expression levels of the Pparg gene and the PPARγ protein in relevant rat models and patients are ongoing.
Funding
- Private Foundation Support