Abstract: PO1199
The Tyrosine Kinase Inhibitor Nintedanib Ameliorates Autosomal Dominant Polycystic Kidney Disease
Session Information
- Cystic Kidney Disease - I
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1001 Genetic Diseases of the Kidneys: Cystic
Authors
- Jamadar, Abeda, University of Kansas Medical Center, Kansas City, Kansas, United States
- Rao, Reena, University of Kansas Medical Center, Kansas City, Kansas, United States
Background
Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease and is characterized by progressive growth of fluid-filled cysts in the kidneys. Growth factor binding to receptor tyrosine kinases (RTKs) are known to stimulate cell proliferation and cyst growth in PKD. In the current study we tested the effect of Nintedanib, an RTK inhibitor and FDA approved drug for non-small cell lung carcinoma and idiopathic lung fibrosis, in mouse models of ADPKD. Nintedanib is a triple RTK inhibitor which targets vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR).
Methods
The effect of Nintedanib on renal cyst growth and fibrosis was tested in two orthologous models of ADPKD, the Pkd1f/fPkhd1Cre mouse, and Pkd1RC/RC mouse. Nintedanib treatment (20 mg/Kg on alternate days by intraperitoneal injections) was from postnatal day P10 to P18 in Pkd1f/fPkhd1Cre mice and in for 8 weeks starting at the age of 3 months in Pkd1RC/RC mice. In vitro studies were performed using primary culture human ADPKD renal cystic epithelial cells and renal myofibroblasts.
Results
Nintedanib treatment significantly reduced kidney-to-body weight ratio, renal cystic index, cystic epithelial cell proliferation and blood urea nitrogen levels compared to vehicle treated Pkd1f/fPkhd1Cre and Pkd1RC/RC mice. Western blot data indicates reduction in the phosphorylation of ERK1/2, AKT, STAT3 and mTOR activation and pro-proliferative factors, including Yes associated protein (YAP), c-Myc and Cyclin D1 protein levels. Moreover, nintedanib treatment significantly reduced renal fibrosis in Pkd1RC/RC mice, however, fibrosis in Pkd1f/fPkhd1Cre mice remained unaffected. In vitro data suggests that nintedanib significantly reduced proliferation and cyst size of human ADPKD cystic epithelial cells as well as cell viability and migration of human ADPKD renal myofibroblasts.
Conclusion
The results suggest that Nintedanib is effective in reducing cyst growth and may be repurposed to treat ADPKD.
Funding
- NIDDK Support