Cilia to basement membrane signalling is a biomechanical driver of autosomal dominant polycystic kidney disease

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Mazloum, Manal | Lapin, Brice | Viau, Amandine | Alghamdi, Rushdi | Burtin, Martine | Houillier, Pascal | Cheval, Lydie | Crambert, Gilles | Aka, Amandine | Kuehn, E. Wolfgang | Cohen, Camille | Descroix, Stéphanie | Busch, Tilman | Köttgen, Michael | Garbay, Serge | Verpont, Marie-Christine | Lelongt, Brigitte | Coscoy, Sylvie | Terzi, Fabiola | Bienaimé, Frank

Edité par CCSD -

Autosomal dominant polycystic kidney disease (ADPKD), which affects around 4 million patients worldwide, is characterized by the formation of multiple tubule derived cysts, which grossly enlarge both kidneys and progressively compromise renal function. ADPKD mainly results from mutations in PKD1 , leading to the loss of polycystin-1 protein, which localizes to primary cilia. Primary cilia are required for cyst formation but the biomechanical changes underlying cystogenesis upon loss of polycytin-1 are unknown. We find that cilia and polycystin-1 shape the tubular basement membrane (TBM). Combining orthologous mouse models with a tubule-on-chip approach allowing manipulations of TBM stiffness, we find that cilia regulate the composition and biomechanical properties of the TBM. In the setting of polycytin-1 loss, reduced TBM stiffness and increased luminal pressure act as biomechanical drivers of cyst formation. These findings suggest a novel biomechanical model for ADPKD and unveil that cilia to TBM signalling controls kidney shape.

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