A 'dynamic' tissue model of glomerular filtration barrier maintenance, adaptation and potential pathways to failure

Azin Azadi

The glomerular filtration barrier (GFB), within the kidney, is known to act as a filter. It must work effectively over its lifespan, avoiding common filter problems such as clogging. Previous mathematical studies mostly just considered how the GFB acts as a size and charge selective barrier. In contrast, here the aim is how the GFB continues to work long-term, despite its environmental changes. The overarching hypothesis presented here is that the tissue is continuously renewing, as podocyte-synthesized molecules are transported ‘upstream’ against the filtrate across the glomerular basement membrane (GBM) to exit via endothelial fenestrae. We refer to this as a ‘dynamic’ tissue, rather than the common static view of the GFB as a simple filter. This then provides a conceptual model to understand how the GFB works long-term. We use computational modelling to (i) test this conceptual model, (ii) integrate and quantify the various biological, biochemical and biophysical processes involved and (iii) predict key model parameter values that are linking to the structural/functional features of GFB. This approach helped identify potential control mechanisms to maintain GFB functional properties against a constant challenges. It also reveals potential pathways to GFB ‘failure’ or pathology. We found there is a constant gradient in the negative fixed charge (NFC) from podocytes to endothelial, which is the main driver for rapid transport of heperan sulfate proteoglycans (HSPGs) against plasma flow. This HSPG flux is a potential anti-clogging mechanism and may enable podocytes-to-endothelial cell upstream crosstalk. We demonstrated that the existence of a constant gradient NFC distribution is beneficial to albumin sieving rate compared to a constant NFC (as assumed in past models). We argue that the role of podocytes slit diaphragms is to retain GBM extracellular matrix proteins, rather than albumin-exclusion barrier. Results are significant in terms of understanding GFB maintenance, adaption and pathology.

A 'dynamic' tissue model of glomerular filtration barrier maintenance, adaptation and potential pathways to failure

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