Altered ciliary morphology reduces mechanosensation in a cystic kidney model as indicated by a mathematical model

Abstract

Abstract This study investigates the biomechanical properties of primary cilia in healthy kidneys and an early-stage cystic kidney model (CKM), focusing on their role in flow-mediated mechanosensation. Morphological analysis showed that CKM cilia are longer, more curved, and exhibit disrupted axonemal integrity compared with normal cilia. To evaluate the effect of such structural changes on bending and stiffness, which may affect the drag force, shear stress and PC1/PC2 complex activation, we developed a mathematical model simulating urine-flow-induced drag. The model predicts that longer and curved cilia experience only one-fourth of the drag force of shorter and straight cilia under identical flow conditions. Remarkably, addition of 5% glucose to drinking water, which was reported to increase water intake, was predicted by the model to elevate urine flow to levels sufficient to partially normalize ciliary length and tubular morphology in CKM kidneys. These findings indicate that ciliary deformation impairs mechanosensation, contributing to cystogenesis, and that restoring mechanical stimulation may mitigate disease progression. Beyond estimating the urine volume required for therapeutic effect, the model offers a framework for developing interventions targeting ciliary mechanotransduction, which could be particularly useful when fluid-loading strategies are not feasible. This approach highlights the potential of combining morphological analysis, biophysical modeling, and mechanobiology to better understand and treat early cystic kidney disease.