{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T22:05:19Z","timestamp":1790546719042,"version":"4.1.0"},"reference-count":42,"publisher":"National Academy of Sciences","issue":"51","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2009,12,22]]},"abstract":"<jats:p>\n                    Polycystic kidney disease (PKD) is a common human genetic disease with severe medical consequences. Although it is appreciated that the cilium plays a central role in PKD, the underlying mechanism for PKD remains poorly understood and no effective treatment is available. In zebrafish, kidney cyst formation is closely associated with laterality defects and body curvature. To discover potential drug candidates and dissect signaling pathways that interact with ciliary signals, we performed a chemical modifier screen for the two phenotypes using zebrafish\n                    <jats:italic>\n                      pkd2\n                      <jats:sup>hi4166<\/jats:sup>\n                    <\/jats:italic>\n                    and\n                    <jats:italic>\n                      ift172\n                      <jats:sup>hi2211<\/jats:sup>\n                    <\/jats:italic>\n                    models.\n                    <jats:italic>pkd2<\/jats:italic>\n                    is a causal gene for autosomal dominant PKD and\n                    <jats:italic>ift172<\/jats:italic>\n                    is essential for building and maintaining the cilium. We identified trichostatin A (TSA), a pan-HDAC (histone deacetylase) inhibitor, as a compound that affected both body curvature and laterality. Further analysis verified that TSA inhibited cyst formation in\n                    <jats:italic>pkd2<\/jats:italic>\n                    knockdown animals. Moreover, we demonstrated that inhibiting class I HDACs, either by valproic acid (VPA), a class I specific HDAC inhibitor structurally unrelated to TSA, or by knocking down\n                    <jats:italic>hdac1<\/jats:italic>\n                    , suppressed kidney cyst formation and body curvature caused by\n                    <jats:italic>pkd2<\/jats:italic>\n                    deficiency. Finally, we show that VPA was able to reduce the progression of cyst formation and slow the decline of kidney function in a mouse ADPKD model. Together, these data suggest body curvature may be used as a surrogate marker for kidney cyst formation in large-scale high-throughput screens in zebrafish. More importantly, our results also reveal a critical role for HDACs in PKD pathogenesis and point to HDAC inhibitors as drug candidates for PKD treatment.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0911987106","type":"journal-article","created":{"date-parts":[[2009,12,4]],"date-time":"2009-12-04T22:05:25Z","timestamp":1259964325000},"page":"21819-21824","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":181,"title":["Chemical modifier screen identifies HDAC inhibitors as suppressors of PKD models"],"prefix":"10.1073","volume":"106","author":[{"given":"Ying","family":"Cao","sequence":"first","affiliation":[{"name":"Departments of Genetics and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Semanchik","sequence":"additional","affiliation":[{"name":"Departments of Genetics and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung Hun","family":"Lee","sequence":"additional","affiliation":[{"name":"Departments of Genetics and"},{"name":"Internal Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Somlo","sequence":"additional","affiliation":[{"name":"Departments of Genetics and"},{"name":"Internal Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo Emilio","family":"Barbano","sequence":"additional","affiliation":[{"name":"Department of Mathematics, Yale University, 10 Hillhouse Avenue, New Haven, CT 06520"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald","family":"Coifman","sequence":"additional","affiliation":[{"name":"Department of Mathematics, Yale University, 10 Hillhouse Avenue, New Haven, CT 06520"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoxia","family":"Sun","sequence":"additional","affiliation":[{"name":"Departments of Genetics and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2009,12,22]]},"reference":[{"key":"e_1_3_3_1_2","first-page":"521","volume-title":"Diseases of the Kidney","author":"Gabow P","year":"1997","unstructured":"P Gabow, J Grantham Diseases of the Kidney, eds R Schrier, C Gottschalk (Little Brown and Co., Boston), pp. 521\u2013560 (1997)."},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(94)90137-6"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.272.5266.1339"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0962-8924(02)02410-8"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0955-0674(02)00012-1"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm952"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.01240"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad946701"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.01663"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.01772"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.125.23.4655"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2007.11.003"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2008.02.034"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M101287200"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1126\/stke.2001.64.re1"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(03)00511-7"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(02)00869-2"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.128.13.2509"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature00849"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81705-5"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/368750a0"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)44885-X"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2007.10.045"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.20168"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.01166"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.01881"},{"key":"e_1_3_3_27_2","first-page":"345","article-title":"Compressive Mahalanobis classifiers. 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