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Pharmacological Npt2a Inhibition Causes Phosphaturia and Reduces Plasma Phosphate in Mice with Normal and Reduced

Linto Thomas1, Jianxiang Xue1, Sathish Kumar Murali2

  • 1Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, Florida; and.

Journal of the American Society of Nephrology : JASN
|August 15, 2019
PubMed
Abstract

Insights

A new Npt2a inhibitor effectively increased phosphate excretion and lowered plasma phosphate levels in normal and chronic kidney disease (CKD) mouse models. This finding highlights a potential therapeutic target for managing hyperphosphatemia in CKD patients.

Area of Science:

  • Nephrology
  • Pharmacology
  • Biochemistry

Background:

  • Kidney function is crucial for phosphate homeostasis.
  • Chronic kidney disease (CKD) often leads to hyperphosphatemia.
  • Current treatments for hyperphosphatemia, including dietary restriction and phosphate binders, have limitations.

Purpose of the Study:

  • To evaluate the efficacy of PF-06869206, an orally bioavailable Npt2a inhibitor, in normal and CKD mouse models.
  • To assess the dose-dependent effects of Npt2a inhibition on urinary excretion of electrolytes and minerals.
  • To investigate the impact of Npt2a inhibition on plasma levels of phosphate, PTH, and FGF-23.

Main Methods:

  • Administered PF-06869206 to normal mice and a 5/6 subtotal nephrectomy (CKD) mouse model.
  • Measured urinary excretion of sodium, chloride, potassium, phosphate, and calcium.
  • Analyzed plasma phosphate, calcium, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF-23) levels.

Main Results:

  • Npt2a inhibition dose-dependently increased urinary phosphate, calcium, sodium, and chloride excretion in normal mice.
  • Plasma phosphate and PTH levels decreased significantly post-treatment, returning to baseline within 24 hours.
  • Similar, though reduced in magnitude, effects were observed in the CKD mouse model.

Conclusions:

  • Npt2a inhibition is a promising therapeutic strategy for managing hyperphosphatemia.
  • The Npt2a inhibitor PF-06869206 demonstrated efficacy in both normal and CKD mouse models.
  • Targeting Npt2a offers a potential new avenue for treating hyperphosphatemia in CKD patients.
Keywords:
Cell & Transport Physiologycalciumchronic kidney diseaseelectrolyteshyperphosphatemiaphosphate uptake

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