Selective pharmacological inhibition of the sodium-dependent phosphate cotransporter NPT2a promotes phosphate excretion

J Clin Invest. 2020 Dec 1;130(12):6510-6522. doi: 10.1172/JCI135665.

Abstract

The sodium-phosphate cotransporter NPT2a plays a key role in the reabsorption of filtered phosphate in proximal renal tubules, thereby critically contributing to phosphate homeostasis. Inadequate urinary phosphate excretion can lead to severe hyperphosphatemia as in tumoral calcinosis and chronic kidney disease (CKD). Pharmacological inhibition of NPT2a may therefore represent an attractive approach for treating hyperphosphatemic conditions. The NPT2a-selective small-molecule inhibitor PF-06869206 was previously shown to reduce phosphate uptake in human proximal tubular cells in vitro. Here, we investigated the acute and chronic effects of the inhibitor in rodents and report that administration of PF-06869206 was well tolerated and elicited a dose-dependent increase in fractional phosphate excretion. This phosphaturic effect lowered plasma phosphate levels in WT mice and in rats with CKD due to subtotal nephrectomy. PF-06869206 had no effect on Npt2a-null mice, but promoted phosphate excretion and reduced phosphate levels in normophophatemic mice lacking Npt2c and in hyperphosphatemic mice lacking Fgf23 or Galnt3. In CKD rats, once-daily administration of PF-06869206 for 8 weeks induced an unabated acute phosphaturic and hypophosphatemic effect, but had no statistically significant effect on FGF23 or PTH levels. Selective pharmacological inhibition of NPT2a thus holds promise as a therapeutic option for genetic and acquired hyperphosphatemic disorders.

Keywords: Chronic kidney disease; Endocrinology; Genetic diseases; Mouse models; Nephrology.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Fibroblast Growth Factors / genetics
  • Fibroblast Growth Factors / metabolism
  • Hyperphosphatemia / genetics
  • Hyperphosphatemia / metabolism*
  • Hyperphosphatemia / pathology
  • Male
  • Mice
  • Mice, Knockout
  • N-Acetylgalactosaminyltransferases / genetics
  • N-Acetylgalactosaminyltransferases / metabolism
  • Phosphates / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Renal Insufficiency, Chronic / genetics
  • Renal Insufficiency, Chronic / metabolism*
  • Renal Insufficiency, Chronic / pathology
  • Sodium-Phosphate Cotransporter Proteins, Type IIa* / antagonists & inhibitors
  • Sodium-Phosphate Cotransporter Proteins, Type IIa* / genetics
  • Sodium-Phosphate Cotransporter Proteins, Type IIa* / metabolism

Substances

  • Phosphates
  • Slc34a1 protein, mouse
  • Sodium-Phosphate Cotransporter Proteins, Type IIa
  • Fibroblast Growth Factors
  • fibroblast growth factor 23
  • N-Acetylgalactosaminyltransferases
  • polypeptide N-acetylgalactosaminyltransferase