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

Area of Science:

• Genetics
• Molecular Biology
• Nephrology

Background:

• Autosomal dominant polycystic kidney disease (ADPKD) is a genetic kidney disorder caused by mutations in PKD1 or PKD2.
• Mutations disrupt the polycystin complex, leading to uncontrolled cyst growth and kidney dysfunction.
• Previous studies suggested Hedgehog (Hh) signaling inhibition could reduce cyst severity in ADPKD models.

Purpose of the Study:

• To investigate the role of Hedgehog (Hh) signaling in ADPKD pathogenesis.
• To determine if Hh pathway components mediate the cilia-dependent cyst activation (CDCA) signal in ADPKD.

Main Methods:

• A Pkd1 hypomorphic mouse model was used.
• Conditional deletion of Hh pathway components (Gli1, Gli2, Gli3, Smo) was induced using tamoxifen-inducible Cre-Lox recombination.
• Kidney weight assessment and microcomputed tomography (micro-CT)-based 3D imaging were employed to evaluate cystic severity.

Main Results:

• Contrary to expectations, inactivation of Gli1 and Smo significantly increased cystogenesis.
• Inactivation of Gli2 and Gli3 did not show a significant effect on cystogenesis.

Conclusions:

• Hedgehog (Hh) signaling does not appear to mediate the cilia-dependent cyst activation (CDCA) signal in ADPKD.
• These findings challenge the previously hypothesized role of Hh signaling in ADPKD progression.