The Inability of Podocytes to Proliferate: Cause, Consequences, and Origin

This study presents a theoretical analysis of the problems related to the inability of podocytes to proliferate. The basis of these problems is the very high rate of glomerular filtration. Podocytes do not in general die by apoptosis or necrosis but are lost by detachment from the glomerular basement membrane (GBM) as viable cells. Podocytes situated on the outside of the filtration barrier and attached to the GBM only by their foot processes are permanently exposed to the flow dynamic forces of the high filtration rate tending to detach them from the GBM. The major challenge seems to consist of the high shear stresses on the foot processes within the filtration slits due to filtrate flow. Healthy podocytes are able to resist this challenge, injured podocytes are not, and may undergo foot process detachment, leading to a gap in the podocyte cover of the GBM. This represents a mortal event. Like a dam break, such a leak cannot be repaired. The ongoing exposure to filtrate flow prevents any attempt to close the gap, thus preventing any regeneration including cell proliferation. An improvement of this precarious situation consists of healing by scarring that may involve only one lobule of the glomerulus, permitting the remaining lobules to maintain filtration. An answer to the question of which waste product requires such a high filtration rate for its excretion may be in the huge quantity of circulating peptides, a problem that dates far back in evolution.