Molecular anatomy of the glomerular filtration barrier reveals topology-encoded albumin sieving

Abstract

The kidney filters plasma rapidly while retaining albumin, yet where and how this selectivity is encoded within the glomerular filtration barrier remain unresolved. Here we combine cryo-electron tomography (cryo-ET) of vitrified mouse glomeruli with structure-resolved transport modelling to predict albumin passage from the native three-dimensional architecture of the barrier. Among the three barrier layers, endothelial fenestrae and the flexible Nephrin-Neph1 slit-diaphragm lattice are substantially permeable to albumin. The glomerular basement membrane (GBM) instead provides the dominant restriction through steric exclusion governed by void-network topology. In local GBM reconstructions, water traverses broadly connected void space, whereas narrow throats exclude albumin, leaving few accessible paths. To scale this mechanism to the tissue level, we combine structural statistics from local cryo-ET volumes with mesoscale measurements of GBM heterogeneity to generate representative ensembles. Integrating these ensembles with other layers predicts whole-barrier albumin sieving in close agreement with an independent measurement. The topology-driven mechanism also explains early filtration failure in Alport syndrome mice, in which collagen-IV disruption remodels the GBM network and opens albumin-accessible paths while cellular interfaces remain preserved. These findings identify the structural origin of glomerular albumin selectivity and establish a quantitative route from locally resolved architecture to tissue-scale physiology.