Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Selective pharmacological inhibition of the sodium-dependent phosphate cotransporter NPT2a promotes phosphate excretion
Valerie Clerin, … , Monica Reyes, Harald Jüppner
Valerie Clerin, … , Monica Reyes, Harald Jüppner
Published August 27, 2020
Citation Information: J Clin Invest. 2020;130(12):6510-6522. https://doi.org/10.1172/JCI135665.
View: Text | PDF
Research Article Endocrinology Nephrology Article has an altmetric score of 3

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

  • Text
  • PDF
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.

Authors

Valerie Clerin, Hiroshi Saito, Kevin J. Filipski, An Hai Nguyen, Jeonifer Garren, Janka Kisucka, Monica Reyes, Harald Jüppner

×

Figure 7

Long-term administration of PF-06869206 elicits sustained daily increases in fractional excretion of phosphate and reductions in plasma phosphate in CKD rats.

Options: View larger image (or click on image) Download as PowerPoint
Long-term administration of PF-06869206 elicits sustained daily increase...
(A) Sprague Dawley rats with CKD due to right unilateral 5/6 nephrectomy (Right UNx) were treated once daily for 8 weeks with PF-06869206 (300 mg/kg/day, n = 12 rats, blue line) or vehicle (n = 12 rats, red line). FEPi (B) and plasma phosphate (C) were derived from analysis of urine and blood samples collected 4 hours after the first treatment dose on study day 1 and on study days 7, 21, 35, and 49. CKD rats receiving 50 mg/kg/day of the clinical drug losartan (n = 12 rats, purple line) for 8 weeks were included for comparison with PF-06869206–treated animals. Sham-operated rats treated with vehicle once daily for 8 weeks served as controls (n = 8, black line). Data are shown as the mean ± SEM. * P < 0.05 versus vehicle-treated 5/6 nephrectomized rats, by 1-way ANOVA.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Posted by 3 X users
Highlighted by 1 platforms
23 readers on Mendeley
See more details