Reduction of elevated Gli3 does not alter the progression of autosomal recessive polycystic kidney disease
Abstract 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 PKHD1, and clinically more severe than the more common autosomal dominant PKD (ADPKD). Prior studies have impl...
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2025-01-01
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| Online Access: | https://doi.org/10.14814/phy2.70191 |
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| author | Lauren G. Russell Maria Kolatsi‐Joannou Laura Wilson Jennifer C. Chandler Nuria Perretta Tejedor Georgie Stagg Karen L. Price Christopher J. Rowan Tessa Crompton Norman D. Rosenblum Paul J. D. Winyard David A. Long |
| author_facet | Lauren G. Russell Maria Kolatsi‐Joannou Laura Wilson Jennifer C. Chandler Nuria Perretta Tejedor Georgie Stagg Karen L. Price Christopher J. Rowan Tessa Crompton Norman D. Rosenblum Paul J. D. Winyard David A. Long |
| author_sort | Lauren G. Russell |
| collection | DOAJ |
| description | Abstract 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 PKHD1, 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 Cpk mice which phenocopy ARPKD and generated a PKHD1‐mutant spheroid model in human collecting ducts. Significantly elevated levels of the Hh transcriptional effector Gli3 were found in Cpk mice, a finding replicated in PKHD1‐mutant spheroids. In Cpk mice, total GLI3 and GLI3 repressor protein levels were also increased. Reduction of increased Gli3 levels via heterozygous genetic deletion in Cpk mice did not affect cyst formation. Additionally, lowering GLI3 transcripts to wildtype levels did not influence PKHD1‐mutant spheroid size. Collectively, these data suggest attenuation of elevated Gli3 does not modulate murine and human models of ARPKD. |
| format | Article |
| id | doaj-art-cc449d2cc43d401d96aef289d21c7e13 |
| institution | Kabale University |
| issn | 2051-817X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Physiological Reports |
| spelling | doaj-art-cc449d2cc43d401d96aef289d21c7e132025-01-27T13:49:52ZengWileyPhysiological Reports2051-817X2025-01-01132n/an/a10.14814/phy2.70191Reduction of elevated Gli3 does not alter the progression of autosomal recessive polycystic kidney diseaseLauren G. Russell0Maria Kolatsi‐Joannou1Laura Wilson2Jennifer C. Chandler3Nuria Perretta Tejedor4Georgie Stagg5Karen L. Price6Christopher J. Rowan7Tessa Crompton8Norman D. Rosenblum9Paul J. D. Winyard10David A. Long11Developmental Biology and Cancer Research and Teaching Department University College London, Great Ormond Street Institute of Child Health London UKDevelopmental Biology and Cancer Research and Teaching Department University College London, Great Ormond Street Institute of Child Health London UKDevelopmental Biology and Cancer Research and Teaching Department University College London, Great Ormond Street Institute of Child Health London UKDevelopmental Biology and Cancer Research and Teaching Department University College London, Great Ormond Street Institute of Child Health London UKDevelopmental Biology and Cancer Research and Teaching Department University College London, Great Ormond Street Institute of Child Health London UKDevelopmental Biology and Cancer Research and Teaching Department University College London, Great Ormond Street Institute of Child Health London UKDevelopmental Biology and Cancer Research and Teaching Department University College London, Great Ormond Street Institute of Child Health London UKDepartment of Paediatrics, Program in Developmental and Stem Cell Biology, Hospital for Sick Children University of Toronto Toronto Ontario CanadaInfection, Immunity and Inflammation Research and Teaching Department University College London, Great Ormond Street Institute of Child Health London UKDepartment of Paediatrics, Program in Developmental and Stem Cell Biology, Hospital for Sick Children University of Toronto Toronto Ontario CanadaDevelopmental Biology and Cancer Research and Teaching Department University College London, Great Ormond Street Institute of Child Health London UKDevelopmental Biology and Cancer Research and Teaching Department University College London, Great Ormond Street Institute of Child Health London UKAbstract 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 PKHD1, 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 Cpk mice which phenocopy ARPKD and generated a PKHD1‐mutant spheroid model in human collecting ducts. Significantly elevated levels of the Hh transcriptional effector Gli3 were found in Cpk mice, a finding replicated in PKHD1‐mutant spheroids. In Cpk mice, total GLI3 and GLI3 repressor protein levels were also increased. Reduction of increased Gli3 levels via heterozygous genetic deletion in Cpk mice did not affect cyst formation. Additionally, lowering GLI3 transcripts to wildtype levels did not influence PKHD1‐mutant spheroid size. Collectively, these data suggest attenuation of elevated Gli3 does not modulate murine and human models of ARPKD.https://doi.org/10.14814/phy2.70191autosomal recessive polycystic kidney diseasecystogenesishedgehog signalinghuman modelmouse model |
| spellingShingle | Lauren G. Russell Maria Kolatsi‐Joannou Laura Wilson Jennifer C. Chandler Nuria Perretta Tejedor Georgie Stagg Karen L. Price Christopher J. Rowan Tessa Crompton Norman D. Rosenblum Paul J. D. Winyard David A. Long Reduction of elevated Gli3 does not alter the progression of autosomal recessive polycystic kidney disease Physiological Reports autosomal recessive polycystic kidney disease cystogenesis hedgehog signaling human model mouse model |
| title | Reduction of elevated Gli3 does not alter the progression of autosomal recessive polycystic kidney disease |
| title_full | Reduction of elevated Gli3 does not alter the progression of autosomal recessive polycystic kidney disease |
| title_fullStr | Reduction of elevated Gli3 does not alter the progression of autosomal recessive polycystic kidney disease |
| title_full_unstemmed | Reduction of elevated Gli3 does not alter the progression of autosomal recessive polycystic kidney disease |
| title_short | Reduction of elevated Gli3 does not alter the progression of autosomal recessive polycystic kidney disease |
| title_sort | reduction of elevated gli3 does not alter the progression of autosomal recessive polycystic kidney disease |
| topic | autosomal recessive polycystic kidney disease cystogenesis hedgehog signaling human model mouse model |
| url | https://doi.org/10.14814/phy2.70191 |
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