Cilia to basement membrane signaling is a biomechanical driver in models of autosomal dominant polycystic kidney disease
Autosomal dominant polycystic kidney disease (ADPKD), the leading genetic cause of kidney failure, results from loss-of-function mutations in PKD1, encoding polycystin-1 (PC1). PC1 localizes to the primary cilium. In the absence of PC1, adverse signaling from the primary cilium orchestrates cyst formation, but the biomechanical underpinnings of this cilia-dependent cyst activation (CDCA) remain unclear. Combining tubule-specific orthologous mouse models with a tubule-on-chip platform, we show that PC1 and cilia govern the composition, mechanical properties and shape of the tubular basement membrane (TBM), the principal rigid determinant of tubule geometry. PC1 loss triggers TBM thinning, heparan sulfate enrichment and deformation, leading to distension, preferentially of the distal nephron. These changes are driven by a cilia-dependent transcriptional program, with GLIS2 - a key CDCA effector - participating as a downstream mediator. Reduction of TBM stiffness amplifies Pkd1-/- tubule-on-chip dilation and increases cyst formation in vivo. Conversely, increasing luminal pressure through ureteral obstruction induces disproportionate distension of Pkd1-deficient tubules and triggers an irreversible cystogenic program. Together, these findings establish a TBM-centered biomechanical model of ADPKD in which tubule deformation is governed by both basolateral and luminal mechanical factors, and identify the cilium-TBM axis, operating in part through GLIS2, as a central driver of cystogenesis.
Authors
- Tilman Busch
- Sylvie Coscoy (ORCID: https://orcid.org/0000-0003-3963-3609)
- Stéphanie Descroix (ORCID: https://orcid.org/0000-0003-0027-352X)
- Brice Lapin
- Nicolas Cagnard (ORCID: https://orcid.org/0000-0002-9051-1896)
- Marie‐Christine Verpont
- Gilles Crambert (ORCID: https://orcid.org/0000-0001-7065-9124)
- Pascal Houillier (ORCID: https://orcid.org/0000-0003-4953-6917)
- Fabiola Terzi (ORCID: https://orcid.org/0000-0001-6107-8125)
- Michael Köttgen (ORCID: https://orcid.org/0000-0003-2406-5039)
- Brigitte Lelongt (ORCID: https://orcid.org/0000-0002-9308-8798)
- Stefan Somlo (ORCID: https://orcid.org/0000-0001-5062-4629)
- Serge Garbay (ORCID: https://orcid.org/0000-0002-1396-8438)
- Lydie Cheval (ORCID: https://orcid.org/0000-0003-2957-6487)
- Frank Bienaimé (ORCID: https://orcid.org/0000-0002-8666-2042)
- Christoph Schell (ORCID: https://orcid.org/0000-0001-5344-624X)
- Amandine Viau (ORCID: https://orcid.org/0000-0003-2890-7897)
- Michael Rehman (ORCID: https://orcid.org/0000-0002-2660-7682)
- Jessica Vandensteen
- Manal Mazloum (ORCID: https://orcid.org/0000-0001-9733-3781)
- Rushdi Alghamdi
- Karim Ourahmoun
- E. Wolfgang Kuehn (ORCID: https://orcid.org/0000-0002-7753-9616)
- Rui Benedito (ORCID: https://orcid.org/0000-0003-2458-3055)
- Ellie Tang
- Camille Cohen
- Vicky Scata
- Amandine Aka
- Martine Burtin
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université Paris Cité (FR)
- Université Paris Sciences et Lettres (FR)
- Angiogenesis Foundation (US)
- University Medical Center Freiburg (DE)
- Yale University (US)
- Sorbonne Université (FR)
- Institut Necker Enfants Malades (FR)
- Centre de Recherche des Cordeliers (FR)
- Centre de Recherche sur l'Inflammation (FR)
- Institut du Cerveau (FR)
- Institut des Maladies Génétiques Imagine (FR)
- Hôpital Tenon (FR)
- Maladies rénales fréquentes et rares : des mécanismes moléculaires à la médecine personnalisée
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2026-06-30
- DOI
- https://doi.org/10.1172/jci196814
- Primary Topic
- Genetic and Kidney Cyst Diseases
- Type
- article
- Field-Weighted Citation Impact
- 0.00