Abstract: TH-PO542
Inhibition of Sodium Phosphate Transporter Npt2a Increases Urinary Phosphate Excretion and Improves Experimental Vascular Calcification in Rats
Session Information
- Bone and Mineral Metabolism: Basic
November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Bone and Mineral Metabolism
- 401 Bone and Mineral Metabolism: Basic
Authors
- Klar, Juergen, Bayer AG, Wuppertal, Germany
- Giese, Anja, Bayer AG, Berlin, Germany
- Ehrmann, Alexander, Bayer AG, Wuppertal, Germany
- Thiel, Christoph, Bayer AG, Wuppertal, Germany
- Riedl, Bernd, Bayer AG, Wuppertal, Germany
- Eitner, Frank, Bayer AG, Wuppertal, Germany
Background
A dysregulated phosphate homeostasis is strongly associated with mortality, cardiovascular events and vascular calcification, particularly in patients suffering from CKD. Inhibition of the tubular phosphate transporter Npt2a provides a novel and unique mechanism to address phosphate homeostasis imbalance.
Methods
Npt2a activity was measured in a cell based assay, using a stable CHO cell line with inducible Npt2a expression. Male Wistar rats were used for all experiments. Healthy rats were treated orally with BAY 767, a potent Npt2a inhibitor developed at Bayer AG. Vascular calcification was induced by administration of a pan-FGFR inh. (25mg/kg) for 10 days.
Results
BAY 767 was identified as potent Npt2a inhibitor, with an IC50 of 2.9/6 nM on rat/ human Npt2a, respectively, selective over Npt2b, Npt2c and Pit-1. Single dose treatments of healthy rats resulted in a significant, dose-dependent increase in urinary phosphate excretion within 16h. Multiple dose treatments (3d) significantly reduced plasma phosphate levels from 2.0 mmol/ L to 1.6 mmol/ L at the highest tested dose. Congruent levels of FGF-23 as well as PTH were decreased to 46% and 43% as compared to untreated controls, respectively. In an experimental vascular calcification model, treatment with the Npt2a inhibitor significantly inhibited vascular calcification and normalized plasma phosphate levels in comparison to untreated rats that developed massive vascular calcification and hyperphosphatemia. In the same model 2.2% lanthanum carbonate was not beneficial with respect to vascular calcification.
Conclusion
Our results show for the first time that treatment with a Npt2a inhibitor improves vascular calcification by addressing urinary phosphate excretion and phosphate homeostasis in rats.
Npt2a inhibition may provide a new therapeutic principle for patients suffering from disbalanced phosphate homeostasis and vascular calcifications, including CKD patients.
Funding
- Commercial Support –