TY - JOUR
T1 - Pyrimethamine inhibits adult polycystic kidney disease by modulating STAT signaling pathways
AU - Takakura, Ayumi
AU - Nelson, Erik A.
AU - Haque, Nadeem
AU - Humphreys, Benjamin D.
AU - Zandi-Nejad, Kambiz
AU - Frank, David A.
AU - Zhou, Jing
N1 - Funding Information:
This work was supported by grants from the National Institutes of Health (DK51050 and DK40703) to J.Z. and DK074030 to the Harvard Center of Polycystic Kidney Disease (J.Z. and A.T.) and Scientist Development Grant from American Heart Association to A.T.
PY - 2011/11
Y1 - 2011/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=80053939641&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddr338
DO - 10.1093/hmg/ddr338
M3 - Article
C2 - 21821671
AN - SCOPUS:80053939641
SN - 0964-6906
VL - 20
SP - 4143
EP - 4154
JO - Human molecular genetics
JF - Human molecular genetics
IS - 21
M1 - ddr338
ER -