title: Pyrimethamine inhibits adult polycystic kidney disease by modulating STAT signaling pathways.
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.
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, USA. atakakura@rics.bwh.harvard.edu
authors.forename: Ayumi
authors.initials: A
authors.lastname: Takakura
authors.forename: Erik A
authors.initials: EA
authors.lastname: Nelson
authors.forename: Nadeem
authors.initials: N
authors.lastname: Haque
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Humphreys
authors.forename: Kambiz
authors.initials: K
authors.lastname: Zandi-Nejad
authors.forename: David A
authors.initials: DA
authors.lastname: Frank
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000328:Adult; D000636:Aminosalicylic Acids / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001557:Benzenesulfonates / Q000494:pharmacology; D002460:Cell Line; D003560:Cysts / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D016891:Polycystic Kidney, Autosomal Dominant / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D011739:Pyrimethamine / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000636:Aminosalicylic Acids; D001557:Benzenesulfonates; C520337:NSC 74859; D050796:STAT3 Transcription Factor; D019000:Phosphotyrosine; D011739:Pyrimethamine