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Use of Ultra-high Field MRI in Small Rodent Models of Polycystic Kidney Disease for In Vivo Phenotyping and Drug Monitoring
07:35

Use of Ultra-high Field MRI in Small Rodent Models of Polycystic Kidney Disease for In Vivo Phenotyping and Drug Monitoring

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Pyrimethamine inhibits adult polycystic kidney disease by modulating STAT signaling pathways

Ayumi Takakura1, Erik A Nelson, Nadeem Haque

  • 1Renal Division, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, USA. atakakura@rics.bwh.harvard.edu

Human Molecular Genetics
|August 9, 2011
PubMed

Insights

Autosomal dominant polycystic kidney disease (ADPKD) treatment may involve blocking signal transducer and activator of transcription 3 (STAT3). Pyrimethamine, an anti-parasitic drug, inhibited STAT3 and reduced cyst growth in ADPKD models, suggesting a potential therapy.

Area of Science:

  • Nephrology
  • Genetics
  • Pharmacology

Background:

  • Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited kidney disorder caused by mutations in PKD1.
  • ADPKD leads to kidney cysts and eventual renal failure, with no current specific treatments.
  • Sustained activation of signal transducer and activator of transcription 3 (STAT3) is observed in polycystic kidneys.

Purpose of the Study:

  • To investigate the role of STAT3 in ADPKD pathogenesis.
  • To identify potential therapeutic agents targeting STAT3 for ADPKD treatment.

Main Methods:

  • Chemical library screening to identify STAT3 inhibitors.
  • In vitro studies using human ADPKD cells.
  • In vivo studies using neonatal and adult polycystic kidney disease (PKD) mouse models.

Main Results:

  • Pyrimethamine, an anti-parasitic compound, was identified as a STAT3 inhibitor.
  • Pyrimethamine treatment reduced cell proliferation in human ADPKD cells.
  • Pyrimethamine and a specific STAT3 inhibitor (S3I-201) blocked and reduced renal cyst formation and growth in PKD mouse models.

Conclusions:

  • Polycystin-1 (PC1) negatively regulates STAT3 signaling.
  • Blocking STAT3 signaling with drugs like pyrimethamine shows promise as a novel therapeutic strategy for ADPKD.

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