Pyrimethamine inhibits adult polycystic kidney disease by modulating STAT signaling pathways

A Takakura, EA Nelson, N Haque… - Human molecular …, 2011 - academic.oup.com
A Takakura, EA Nelson, N Haque, BD Humphreys, K Zandi-Nejad, DA Frank, J Zhou
Human molecular genetics, 2011academic.oup.com
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 …
Abstract
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.
Oxford University Press