Abstract: TH-OR042
A NPT2A-Selective Inhibitor Increases Phosphate Excretion in FGF23-Null and CKD Mice
Session Information
- Bone and Mineral Metabolism: Basic Research
November 07, 2019 | Location: 145, Walter E. Washington Convention Center
Abstract Time: 04:42 PM - 04:54 PM
Category: Bone and Mineral Metabolism
- 401 Bone and Mineral Metabolism: Basic
Authors
- Saito, Hiroshi, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States
- Reyes, Monica, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States
- Jüppner, Harald, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States
Background
The sodium-phosphate co-transporters NPT2a and NPT2c play key roles in reabsorbing filtered phosphate in proximal renal tubules thus contributing critically to phosphate (Pi) homeostasis. Expression of both transporters is regulated by parathyroid hormone (PTH) and Fibroblast Growth Factor 23 (FGF23). Consequently, inactivating mutations in FGF23, GALNT3, or KLOTHO lead to tumoral calcinosis because of increased tubular Pi reabsorption resulting in hyperphosphatemia. Increased plasma Pi levels are also observed in disorders with abnormal PTH synthesis or function, i.e. hypoparathyroidism and pseudohypoparathyroidism, respectively. Furthermore, acute and chronic kidney disease (CKD) typically leads to a significant elevation of plasma Pi and FGF23, which are associated with kidney disease progression and increased mortality.
Methods
A novel NPT2a-selective small molecule inhibitor, PF-06869206, which reduces phosphate uptake in human proximal tubular cells was given by oral gavage (10-500 mg/kg) to wild-type mice, to mice lacking either Npt2a, Npt2c, or Fgf23, and to mice with folic acid-induced AKI or adenine-induced CKD. Plasma Pi levels were measured at different time points after PF-06869206 administration, along with urinary Pi and creatinine.
Results
Administration of PF-06869206was well-tolerated and elicited a dose-dependent increase in fractional Pi excretion in wild-type mice that resulted in a reduction of plasma Pi levels by approximately3.0 mg/dl. The increase in urinary Pi excretion and the resulting reduction in plasma Pi after a single oral dose of PF-06869206 (300 mg/kg) was indistinguishable in wild-type mice and in animals lacking Npt2c, while no changes were observed in Npt2a-null mice. Furthermore, in Fgf23-null mice a single dose of the NPT2a inhibitor increased urinary Pi excretion by approximately 4-fold, which reduced plasma Pi levels from 15.8±0.84 to 11.6±0.49 mg/dl. In AKI and CKD mice, treatment with PF-06869206 increased urinary Pi excretion thereby reducing plasma Pi levels.
Conclusion
The selective pharmacological inhibition of NPT2a holds promise as a novel therapeutic option for genetic and acquired hyperphosphatemic disorders.
Funding
- NIDDK Support