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

J Am Soc Nephrol. 2019 Nov;30(11):2128-2139. doi: 10.1681/ASN.2018121250. Epub 2019 Aug 13.

Abstract

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.

Keywords: Cell & Transport Physiology; calcium; chronic kidney disease; electrolytes; hyperphosphatemia; phosphate uptake.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / urine
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Fibroblast Growth Factor-23
  • Fibroblast Growth Factors / blood
  • Hypophosphatemia, Familial / etiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Parathyroid Hormone / blood
  • Phosphates / blood*
  • Renal Insufficiency, Chronic / metabolism*
  • Sodium-Phosphate Cotransporter Proteins, Type IIa / antagonists & inhibitors*

Substances

  • Fgf23 protein, mouse
  • Parathyroid Hormone
  • Phosphates
  • Slc34a1 protein, mouse
  • Sodium-Phosphate Cotransporter Proteins, Type IIa
  • Fibroblast Growth Factors
  • Fibroblast Growth Factor-23
  • Calcium