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. 2025 Oct 15;138(20):jcs264133.
doi: 10.1242/jcs.264133. Epub 2025 Jul 31.

Inhibition of Hedgehog signaling does not mitigate polycystic kidney disease severity in a Pkd1 mutant mouse model

Sean K Gombart  1 , Scott Houghtaling  1 , Tzu-Hua Ho  1 , David R Beier  1   2
Affiliations

Inhibition of Hedgehog signaling does not mitigate polycystic kidney disease severity in a Pkd1 mutant mouse model

Sean K Gombart et al. J Cell Sci. .

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a monogenic disorder caused by mutations in PKD1 or PKD2, encoding polycystin-1 and polycystin-2, respectively. These polycystins form a cilia-localized complex that, when mutated, fails to inhibit an uncharacterized cilia-dependent cyst activation (CDCA) signal. This leads to progressive bilateral cyst growth and ultimately compromised renal function. Previous in vitro and in vivo studies from our group have demonstrated that Hedgehog (Hh) signaling inhibition reduces renal cystic severity in PKD models. To further investigate, we inactivated several Hh pathway components (Gli1, Gli2, Gli3 and Smo) in a Pkd1 hypomorphic mouse model through conditional deletion by tamoxifen-induced Cre-Lox recombination. We assessed cystic severity using kidney weight assessment and a microcomputed tomography (micro-CT)-based 3D imaging assay. Contrary to expectations, inactivation of Gli1 and Smo significantly increased cystogenesis. These findings suggest that Hh signaling does not mediate the CDCA signal.

Keywords: Hedgehog signaling; Mouse disease models; Polycystic kidney disease.

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Conflict of interest statement

Competing interests The authors declare no competing or financial interests.

References

    1. Arroyo, J., Escobar-Zarate, D., Wells, H. H., Constans, M. M., Thao, K., Smith, J. M., Sieben, C. J., Martell, M. R., Kline, T. L., Irazabal, M. V.et al. (2021). The genetic background significantly impacts the severity of kidney cystic disease in the Pkd1(RC/RC) mouse model of autosomal dominant polycystic kidney disease. Kidney Int. 99, 1392-1407. 10.1016/j.kint.2021.01.028 - DOI - PMC - PubMed
    1. Bai, C. B., Auerbach, W., Lee, J. S., Stephen, D. and Joyner, A. L. (2002). Gli2, but not Gli1, is required for initial Shh signaling and ectopic activation of the Shh pathway. Development 129, 4753-4761. 10.1242/dev.129.20.4753 - DOI - PubMed
    1. Benallegue, N., Kebir, H., Kapoor, R., Crockett, A., Li, C., Cheslow, L., Abdel-Hakeem, M. S., Gesualdi, J., Miller, M. C., Wherry, E. J.et al. (2021). The hedgehog pathway suppresses neuropathogenesis in CD4 T cell-driven inflammation. Brain 144, 1670-1683. 10.1093/brain/awab083 - DOI - PMC - PubMed
    1. Blaess, S., Stephen, D. and Joyner, A. L. (2008). Gli3 coordinates three-dimensional patterning and growth of the tectum and cerebellum by integrating Shh and Fgf8 signaling. Development 135, 2093-2103. 10.1242/dev.015990 - DOI - PMC - PubMed
    1. Boletta, A. and Caplan, M. J. (2025). Physiologic mechanisms underlying polycystic kidney disease. Physiol. Rev. 105, 1553-1607. 10.1152/physrev.00018.2024 - DOI - PMC - PubMed

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