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Here we show that STAT6 is aberrantly activated in cyst-lining cells in PKD mouse models. Activation of the STAT6 pathway leads to a positive feedback loop involving auto\/paracrine signaling by IL13 and the IL4\/13 receptor. The presence of IL13 in cyst fluid and the overexpression of IL4\/13 receptor chains suggests a mechanism of sustained STAT6 activation in cysts. Genetic inactivation of STAT6 in a PKD mouse model leads to significant inhibition of proliferation and cyst growth and preservation of renal function. We show that the active metabolite of leflunomide, a drug approved for treatment of arthritis, inhibits STAT6 in renal epithelial cells. Treatment of PKD mice with this drug leads to amelioration of the renal cystic disease similar to genetic STAT6 inactivation. These results suggest STAT6 as a promising drug target for treatment of ADPKD.<\/jats:p>","DOI":"10.1073\/pnas.1111966108","type":"journal-article","created":{"date-parts":[[2011,10,25]],"date-time":"2011-10-25T01:52:20Z","timestamp":1319507540000},"page":"18067-18072","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":74,"title":["Signal transducer and activator of transcription-6 (STAT6) inhibition suppresses renal cyst growth in polycystic kidney disease"],"prefix":"10.1073","volume":"108","author":[{"given":"Erin E.","family":"Olsan","sequence":"first","affiliation":[{"name":"Department of Molecular, Cellular and Developmental Biology and"},{"name":"Neuroscience Research Institute, University of California, Santa Barbara, CA 93106; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sambuddho","family":"Mukherjee","sequence":"additional","affiliation":[{"name":"Department of Molecular, Cellular and Developmental 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