Solute transport through the glomerular filtration barrier: the podocyte slit diaphragms' role in maintaining glomerular basement membrane integrity and podocyte-to-endothelial crosstalk.

Abstract

The glomerular filtration barrier (GFB) is a size- and charge-selective filter regulating the passage of blood-borne solutes into the urinary space. However, solutes within the GFB may also originate from podocyte secretion, including extracellular matrix (ECM) components and signaling molecules. We developed a two-dimensional computational solute transport model incorporating two cross-sectional GFB geometries: one based on averaged rodent data and one reconstructed from a healthy adult human glomerular image. Four cases were examined, defined by the solute's source and its ability to pass the podocyte slit diaphragm. To account for a wide range of solute types, solute mobility, described by the effective diffusion coefficient (Deff), was varied over six orders of magnitude. For blood-borne solutes unable to pass the slit diaphragm, a steep concentration gradient forms, with the highest concentration adjacent to the podocytes. This gradient becomes steeper as Deff decreases, corresponding to larger or less mobile solutes. This finding has implications for barrier clogging and for mechanisms that may increase Deff, including the role of ECM fixed charge density or ECM turnover. For podocyte-synthesized solutes to move against filtrate flow, without being rapidly lost to the urinary space, the model suggests solutes must possess properties preventing passage through the slit diaphragm. This result provides context for the relatively large signaling molecule complexes and ECM components. Together, these findings suggest that the structural organization of the GFB, particularly the slit diaphragm, enables solute distribution and directional transport, and therefore provides insight into GFB maintenance and pathology.