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

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DOI

  • Linto Thomas, Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, Florida, USA.
  • ,
  • Jianxiang Xue, Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, Florida, USA.
  • ,
  • Sathish Kumar Murali
  • Robert A Fenton
  • Jessica A Dominguez Rieg, Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, Florida, USA.
  • ,
  • Timo Rieg, Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, Florida, USA. Electronic address: trieg@health.usf.edu.

BACKGROUND: The kidneys play an important role in phosphate homeostasis. Patients with CKD develop hyperphosphatemia in the later stages of the disease. Currently, treatment options are limited to dietary phosphate restriction and oral phosphate binders. The sodium-phosphate cotransporter Npt2a, which mediates a large proportion of phosphate reabsorption in the kidney, might be a good therapeutic target for new medications for hyperphosphatemia.

METHODS: The authors assessed the effects of the first orally bioavailable Npt2a inhibitor (Npt2a-I) PF-06869206 in normal mice and mice that had undergone subtotal nephrectomy (5/6 Nx), a mouse model of CKD. Dose-response relationships of sodium, chloride, potassium, phosphate, and calcium excretion were assessed in response to the Npt2a inhibitor in both groups of mice. Expression and localization of Npt2a/c and levels of plasma phosphate, calcium, parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF-23) were studied up to 24-hours after Npt2a-I treatment.

RESULTS: In normal mice, Npt2a inhibition caused a dose-dependent increase in urinary phosphate (ED50 approximately 21 mg/kg), calcium, sodium and chloride excretion. In contrast, urinary potassium excretion, flow rate and urinary pH were not affected dose dependently. Plasma phosphate and PTH significantly decreased after 3 hours, with both returning to near baseline levels after 24 hours. Similar effects were observed in the mouse model of CKD but were reduced in magnitude.

CONCLUSIONS: Npt2a inhibition causes a dose-dependent increase in phosphate, sodium and chloride excretion associated with reductions in plasma phosphate and PTH levels in normal mice and in a CKD mouse model.

Original languageEnglish
JournalJournal of the American Society of Nephrology : JASN
Volume30
Issue11
Pages (from-to)2128-2139
Number of pages12
ISSN1046-6673
DOIs
Publication statusPublished - Nov 2019

Bibliographical note

Copyright © 2019 by the American Society of Nephrology.

    Research areas

  • Cell & Transport Physiology, calcium, chronic kidney disease, electrolytes, hyperphosphatemia, phosphate uptake

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