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Autosomal recessive PKD (ARPKD) is a rare form of PKD, caused by mutations in\n                    <jats:italic>PKHD1<\/jats:italic>\n                    , and clinically more severe than the more common autosomal dominant PKD (ADPKD). Prior studies have implicated Hedgehog (Hh) signaling in ADPKD, with increased levels of Hh components in experimental ADPKD and reduced cystogenesis following pharmacological Hh inhibition. In contrast, the role of the Hh pathway in ARPKD is poorly understood. We hypothesized that Hh pathway activity would be elevated during ARPKD pathogenesis, and its modulation may slow disease progression. We utilized\n                    <jats:italic>Cpk<\/jats:italic>\n                    mice which phenocopy ARPKD and generated a\n                    <jats:italic>PKHD1<\/jats:italic>\n                    \u2010mutant spheroid model in human collecting ducts. Significantly elevated levels of the Hh transcriptional effector\n                    <jats:italic>Gli3<\/jats:italic>\n                    were found in\n                    <jats:italic>Cpk<\/jats:italic>\n                    mice, a finding replicated in\n                    <jats:italic>PKHD1<\/jats:italic>\n                    \u2010mutant spheroids. In\n                    <jats:italic>Cpk<\/jats:italic>\n                    mice, total GLI3 and GLI3 repressor protein levels were also increased. Reduction of increased\n                    <jats:italic>Gli3<\/jats:italic>\n                    levels via heterozygous genetic deletion in\n                    <jats:italic>Cpk<\/jats:italic>\n                    mice did not affect cyst formation. Additionally, lowering\n                    <jats:italic>GLI3<\/jats:italic>\n                    transcripts to wildtype levels did not influence\n                    <jats:italic>PKHD1<\/jats:italic>\n                    \u2010mutant spheroid size. Collectively, these data suggest attenuation of elevated Gli3 does not modulate murine and human models of ARPKD.\n                  <\/jats:p>","DOI":"10.14814\/phy2.70191","type":"journal-article","created":{"date-parts":[[2025,1,17]],"date-time":"2025-01-17T02:35:29Z","timestamp":1737081329000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Reduction of elevated\n                    <i>Gli3<\/i>\n                    does not alter the progression of autosomal recessive polycystic kidney disease"],"prefix":"10.14814","volume":"13","author":[{"given":"Lauren G.","family":"Russell","sequence":"first","affiliation":[{"name":"Developmental Biology and Cancer Research and Teaching Department University College London, Great Ormond Street Institute of Child Health  London UK"},{"name":"UCL Centre for Kidney and Bladder Health University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Kolatsi\u2010Joannou","sequence":"additional","affiliation":[{"name":"Developmental Biology and Cancer Research and Teaching Department University College London, Great Ormond Street Institute of Child Health  London UK"},{"name":"UCL Centre for Kidney and Bladder Health University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Wilson","sequence":"additional","affiliation":[{"name":"Developmental Biology and Cancer Research and Teaching Department University College London, Great Ormond Street Institute of Child Health  London UK"},{"name":"UCL Centre for Kidney and Bladder Health University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer C.","family":"Chandler","sequence":"additional","affiliation":[{"name":"Developmental Biology and Cancer Research and Teaching Department University College London, Great Ormond Street Institute of Child Health  London UK"},{"name":"UCL Centre for Kidney and Bladder Health University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nuria Perretta","family":"Tejedor","sequence":"additional","affiliation":[{"name":"Developmental Biology and Cancer Research and Teaching Department University College London, Great Ormond Street Institute of Child Health  London UK"},{"name":"UCL Centre for Kidney and Bladder Health University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgie","family":"Stagg","sequence":"additional","affiliation":[{"name":"Developmental Biology and Cancer Research and Teaching Department University College London, Great Ormond Street Institute of Child Health  London UK"},{"name":"UCL Centre for Kidney and Bladder Health University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen L.","family":"Price","sequence":"additional","affiliation":[{"name":"Developmental Biology and Cancer Research and Teaching Department University College London, Great Ormond Street Institute of Child Health  London UK"},{"name":"UCL Centre for Kidney and Bladder Health University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J.","family":"Rowan","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Program in Developmental and Stem Cell Biology, Hospital for Sick Children University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tessa","family":"Crompton","sequence":"additional","affiliation":[{"name":"Infection, Immunity and Inflammation Research and Teaching Department University College London, Great Ormond Street Institute of Child Health  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norman D.","family":"Rosenblum","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Program in Developmental and Stem Cell Biology, Hospital for Sick Children University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul J. 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