{"doi":"10.14814/phy2.70191","title":"Reduction of elevated\n                    <i>Gli3</i>\n                    does not alter the progression of autosomal recessive polycystic kidney disease","abstract":"<jats:title>Abstract</jats:title>\n                  <jats:p>\n                    Polycystic kidney diseases (PKD) are genetic disorders which disrupt kidney architecture and function. 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                    ‐mutant 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                    ‐mutant 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                    ‐mutant spheroid size. Collectively, these data suggest attenuation of elevated Gli3 does not modulate murine and human models of ARPKD.\n                  </jats:p>","journal":"Physiological Reports","year":2025,"id":644627,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1677996,"name":"Maria Kolatsi‐Joannou","orcid":null,"position":1,"is_corresponding":false},{"id":997250,"name":"Laura Wilson","orcid":"0000-0002-7919-2230","position":2,"is_corresponding":false},{"id":1677997,"name":"Jennifer C. Chandler","orcid":null,"position":3,"is_corresponding":false},{"id":1677998,"name":"Nuria Perretta Tejedor","orcid":null,"position":4,"is_corresponding":false},{"id":1677999,"name":"Georgie Stagg","orcid":null,"position":5,"is_corresponding":false},{"id":1589265,"name":"Karen L. Price","orcid":null,"position":6,"is_corresponding":false},{"id":865930,"name":"Christopher J. Rowan","orcid":"0000-0002-6810-6691","position":7,"is_corresponding":false},{"id":856644,"name":"Tessa Crompton","orcid":"0000-0002-8973-4021","position":8,"is_corresponding":false},{"id":7340,"name":"Norman D. Rosenblum","orcid":"0000-0003-1767-6464","position":9,"is_corresponding":false},{"id":1678000,"name":"Paul J. D. Winyard","orcid":null,"position":10,"is_corresponding":false},{"id":618663,"name":"David A. Long","orcid":"0000-0001-6580-3435","position":11,"is_corresponding":false},{"id":1677995,"name":"Lauren G. Russell","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Reduction of elevated\n                    <i>Gli3</i>\n                    does not alter the progression of autosomal recessive polycystic kidney disease","abstract":"<jats:title>Abstract</jats:title>\n                  <jats:p>\n                    Polycystic kidney diseases (PKD) are genetic disorders which disrupt kidney architecture and function. 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                    ‐mutant 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                    ‐mutant 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                    ‐mutant spheroid size. Collectively, these data suggest attenuation of elevated Gli3 does not modulate murine and human models of ARPKD.\n                  </jats:p>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"39823139","pmcid":"PMC11738646","openalex_id":"https://openalex.org/W4406486847","authors":[],"funders":[{"funder_name":"Kidney Research UK","grant_id":"ST_006_20181123","title":null},{"funder_name":"Wellcome Trust","grant_id":"220895/Z/20/Z","title":null},{"funder_name":"Biotechnology and Biological Sciences Research Council","grant_id":"BB/X512011/1","title":"22ROMITIGATIONFUNDUniversityCollegeLondon"},{"funder_name":"Wellcome Trust","grant_id":"220895","title":"Lymphatic biology in kidney development, health and disease"},{"funder_name":"Canadian Institutes of Health Research","grant_id":"unidentified","title":"unidentified"},{"funder_name":"NIHR Great Ormond Street Hospital Biomedical Research Centre","grant_id":"","title":null},{"funder_name":"NIHR | NIHR Great Ormond Street Hospital Biomedical Research Centre (BRC)","grant_id":"","title":null},{"funder_name":"Canadian Institutes of Health Research","grant_id":"","title":null},{"funder_name":"Gouvernement du Canada | Canadian Institutes of Health Research (IRSC)","grant_id":"","title":null},{"funder_name":"University College London Research Culture Award","grant_id":"","title":null},{"funder_name":"Wellcome Trust","grant_id":"","title":null}],"total_grants":11,"fwci":0.0,"citation_percentile":0.00804099,"influential_citations":0,"citation_trend":[],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.14814/phy2.70191","host_type":"journal"},{"url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.14814/phy2.70191","host_type":"publisher"},{"url":"https://physoc.onlinelibrary.wiley.com/doi/pdf/10.14814/phy2.70191","host_type":"publisher"},{"url":"https://physoc.onlinelibrary.wiley.com/doi/full-xml/10.14814/phy2.70191","host_type":"publisher"},{"url":"https://doi.org/10.14814/phy2.70191","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/39823139","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/11738646","host_type":"repository"},{"url":"https://doaj.org/article/cc449d2cc43d401d96aef289d21c7e13","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11738646/pdf/PHY2-13-e70191.pdf","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC11738646","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC11738646?pdf=render","host_type":"Europe_PMC"},{"url":"http://dx.doi.org/10.14814/phy2.70191","host_type":""}],"fields_of_study":["Genetic and Kidney Cyst Diseases","Hedgehog Signaling Pathway Studies","Epigenetics and DNA Methylation","0301 basic medicine","03 medical and health sciences"],"mesh_terms":["Zinc Finger Protein Gli3","Animals","Disease Models, Animal","Humans","Male","Mice, Inbred C57BL","Nerve Tissue Proteins","Receptors, Cell Surface","Signal Transduction","Polycystic Kidney, Autosomal Recessive","Disease Progression","Mice","Kruppel-Like Transcription Factors","Hedgehog Proteins"],"keywords":["Polycystic kidney disease","Polycystic kidney","Medicine","Disease","Kidney","Bioinformatics","Reduction (mathematics)","GLI3","Endocrinology","Internal medicine","Pathology","Genetics","Biology","Gene","Mouse Model","Hedgehog Signaling","Cystogenesis","Autosomal Recessive Polycystic Kidney Disease","Human Model","Male","Physiology","Kruppel-Like Transcription Factors","Nerve Tissue Proteins","Receptors, Cell Surface","Mice, Inbred C57BL","Mice","Disease Models, Animal","Zinc Finger Protein Gli3","Disease Progression","QP1-981","Animals","Humans","Original Article","Polycystic Kidney, Autosomal Recessive","Signal Transduction"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-09T01:42:35.087770Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}