Evidence for a tubular basement membrane-cilia connection in autosomal dominant polycystic kidney disease pathogenesis.

Abstract

Autosomal dominant polycystic kidney disease (ADPKD), mainly driven by pathogenic variants in PKD1 and PKD2, is the most common inherited cause of kidney failure. Details of ADPKD pathogenesis are incompletely resolved, but primary cilia are an integral component. There is also evidence for changes to the tubular basement membrane (TBM) in early disease. In this issue of the JCI, Mazloum and colleagues link cilia-dependent, PKD1-mediated regulation of the TBM to ADPKD pathogenesis. Using in vivo, ex vivo, tubule-on-chip, and cellular models of ADPKD, they connect cilia-dependent tubule dilation and TBM thinning to early-stage cystogenesis. Moreover, they identify a cilia-dependent TBM remodeling expression signature in affected tubules and suggest that PC1 loss compromises TBM stiffness. By integrating roles for cilia at the apical membrane and extracellular matrix at the basolateral membrane in cystogenesis, this work highlights the TBM as an additional area for investigation of therapeutic and biomarker discovery in ADPKD.