Cilia–to–basement membrane signaling is a biomechanical driver in models of autosomal dominant polycystic kidney disease

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Abstract

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 triggered TBM thinning, heparan sulfate enrichment, and deformation, leading to distension, preferentially of the distal nephron. These changes were driven by a cilia-dependent transcriptional program, with GLIS2 — a key CDCA effector — participating as a downstream mediator. Reduction of TBM stiffness amplified Pkd1–/– tubule-on-chip dilation and increased cyst formation in vivo. Conversely, increasing luminal pressure through ureteral obstruction induced disproportionate distension of Pkd1-deficient tubules and triggered 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

Manal Mazloum, Brice Lapin, Rushdi Alghamdi, Jessica Vandensteen, Martine Burtin, Pascal Houillier, Lydie Cheval, Gilles Crambert, Vicky Scata, Camille Cohen, Christoph Schell, Michael Rehman, Amandine Aka, Karim Ourahmoun, Rui Benedito, E. Wolfgang Kuehn, Stéphanie Descroix, Tilman Busch, Michael Köttgen, Serge Garbay, Marie-Christine Verpont, Ellie Tang, Brigitte Lelongt, Nicolas Cagnard, Stefan Somlo, Sylvie Coscoy, Fabiola Terzi, Amandine Viau, Frank Bienaimé