Russell, Lauren G;
Kolatsi-Joannou, Maria;
Wilson, Laura;
Chandler, Jennifer C;
Perretta Tejedor, Nuria;
Stagg, Georgie;
Price, Karen L;
... Long, David A; + view all
(2025)
Reduction of elevated Gli3 does not alter the progression of autosomal recessive polycystic kidney disease.
Physiological Reports
, 13
(2)
, Article e70191. 10.14814/phy2.70191.
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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.
| Type: | Article |
|---|---|
| Title: | Reduction of elevated Gli3 does not alter the progression of autosomal recessive polycystic kidney disease |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.14814/phy2.70191 |
| Publisher version: | https://doi.org/10.14814/phy2.70191 |
| Language: | English |
| Additional information: | © 2025 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. https://creativecommons.org/licenses/by/4.0/ |
| Keywords: | autosomal recessive polycystic kidney disease, cystogenesis, hedgehog signaling, human model, mouse model |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10203681 |
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