Pyrimethamine inhibits adult polycystic kidney disease by modulating STAT signaling pathways
Open accessAbstract
Autosomal dominant polycystic kidney disease (ADPKD) is a commonly inherited disorder mostly caused by mutations in PKD1, encoding polycystin-1 (PC1). The disease is characterized by development and growth of epithelium-lined cyst in both kidneys, often leading to renal failure. There is no specific treatment for this disease. Here, we report a sustained activation of the transcription factor signal transducer and activator of transcription 3 (STAT3) in ischemic injured and uninjured Pkd1 knockout polycystic kidneys and in human ADPKD kidneys. Through a chemical library screen, we identified the anti-parasitic compound pyrimethamine as an inhibitor of STAT3 function. Treatment with pyrimethamine decreases cell proliferation in human ADPKD cells and blocks renal cyst formation in an adult and a neonatal PKD mouse model. Moreover, we demonstrated that a specific STAT3 inhibitor, S3I-201, reduces cyst formation and growth in a neonatal PKD mouse model. Our results suggest that PC1 acts as a negative regulator of STAT3 and that blocking STAT3 signaling with pyrimethamine or similar drugs may be an attractive therapy for human ADPKD.
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Early studies demonstrated that GLG-801 inhibited STAT3 activation and renal cyst formation in a mouse model of polycystic kidney.
“Early studies demonstrated that GLG-801 inhibited STAT3 activation and renal cyst formation in a mouse model of polycystic kidney (Takakura et al., 2011).”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Takakura et al., 2011
The Introduction reports that pyrimethamine and S3I-201 inhibited cyst formation and growth in adult-onset and neonatal PKD mouse models, respectively. The S3I-201 results also report reduced pSTAT3-positive kidney cells. The paper does not identify either compound as GLG-801 or report these effects for GLG-801, so the named-drug attribution is unsupported. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPyrimethamine was identified as a STAT3 inhibitor using a cell-based functional screen of a Preswick library of compounds.
“It was identified as a STAT3 inhibitor using a cell-based functional screen of a Preswick library of compounds.”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Takakura et al., 2011
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Bharadwaj, U., Kasembeli, M. M., Robinson, P., & Tweardy, D. J. (2020) · Pharmacological Reviews · doi:10.1124/pr.119.018440 · Cited by 314 · see citing works
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Self-citation
- Authors
- Takakura, A., Nelson, E. A., Haque, N., Humphreys, B. D., Zandi-Nejad, K., Frank, D. A., & Zhou, J.
- Affiliations
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Corresponding author
- Takakura, Ayumi
- Zhou, Jing
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-08-05
- Volume
- 20
- Issue
- 21
- Pages
- 4143-4154
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC3188991
- OpenAlex
- W2101454196
- Cited by
- 143
- References
- 2
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 10 · 2023: 4 · 2022: 10 · 2021: 14 · 2020: 15 · 2019: 11 · 2018: 12 · 2017: 9 · 2016: 6 · 2015: 11 · 2014: 11 · 2013: 13 · 2012: 10
- FWCI
- 6.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 40703, P50DK074030, DK 51050, DK074030, R37DK051050, R01DK040703)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
- Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
- Keywords
- autosomal dominant polycystic kidney disease, pyrimethamine, STAT3 signaling, polycystin-1, Pkd1 knockout mice, renal cyst formation, S3I-201, STAT3 inhibitor, cell proliferation, drug repurposing
- MeSH terms
- Adult, Aminosalicylic Acids, Animals, Animals, Newborn, Benzenesulfonates, Cell Line, Cysts, Disease Models, Animal, Humans, Kidney, Phosphorylation, Pyrimethamine, Signal Transduction, Gene Expression, Polycystic Kidney, Autosomal Dominant, Genes, Reporter, Mice, Knockout, Phosphotyrosine, STAT3 Transcription Factor, Mice
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