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

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

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

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Figure 7

Pkd1 deletion alters tubule biomechanics.

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Pkd1 deletion alters tubule biomechanics. (A) Scheme of isolated intact...
(A) Scheme of isolated intact tubule perfusion setting. Adapted from Journal of Clinical Investigation (16). (B and C) Representative images (B) and quantification of the variation in outer tubule diameter induced by a progressive increase in transmural pressure (TM; C) in CDs isolated from 8-week-old control, Pkd1Δtub, and Pkd1Δtub Kif3aΔtub male mice. Each dot represents 1 tubule (mean of 10 measurements per tubule) for a pressure increment. (D) Quantification of the slope of the pressure-diameter curves for each pressure increment in CDs isolated from the same groups of mice. Each dot represents 1 tubule. Student’s t test: *P < 0.05, **P < 0.01. (E and F) Representative images (E) and quantification of the variation in outer tubule diameter induced by incremental increase in TM pressure (F) in PTs isolated from 8-week-old control and Pkd1Δtub mice. Each dot represents 1 tubule (mean of 10 measurements per tubule) for a pressure increment. (G and H) Representative images (G) and quantification of the variation in outer tubule diameter induced by incremental increase in TM pressure (H) in PTs isolated from 12-week-old control, Pkd1Δtub, and Pkd1Δtub Kif3aΔtub mice. Each triangle represents 1 tubule (mean of 10 measurements per tubule) for a pressure increment. (I) Quantification of the slope of the pressure-diameter curves for each pressure increment in PTs isolated from 8- (circles) and 12-week-old (triangles) control, Pkd1Δtub, and Pkd1Δtub Kif3aΔtub mice. PTs from control animals at 8 (blue circle) and 12 weeks (blue triangle) were pooled in analyses. Each symbol represents 1 tubule. Scale bars: 50 μm. One-way ANOVA followed by Tukey-Kramer test: **P < 0.01. Pkd1fl/fl littermates lacking cre or rtTA transgene were used as control.