Role of the podocyte in proteinuria

Abstract

In recent years, the podocyte, with its elaborate cytoarchitecture and slit diaphragm, has been the focus of extensive research, yet its precise role in the glomerular filtration barrier is still debated. There are puzzling observations indicating that a comprehensive mechanistic model for glomerular filtration is still necessary. There is no doubt that podocytes are essential for glomerular filtration barrier integrity. However, most albumin never reaches the podocyte because it is prevented from entering the glomerular filter at the endothelium level. Another puzzling observation is that the glomerular filter never clogs despite its high load of several kilograms of plasma proteins per day. Recently, we proposed a novel model in which an electrical potential difference is generated across the glomerular filtration barrier by filtration. The model offers novel potential solutions to some of the riddles regarding the glomerular filter.

Fig. 1

Glomerular filtration barrier. The filtrate passes the layers of the filter as a laminar, nonturbulent flow along an extracellular route (arrow). Albumin is largely excluded from entering the filter, as indicated by the local albumin concentration on the left. GBM Glomerular basement membrane

Fig. 2

Highly simplified model for the generation of streaming potentials across the glomerular filtration barrier. a The entire cross section of the glomerular filter can be modeled as a single pore. b Higher magnification of the pore. The ionic fluid [cations: sodium (Na⁺), potassium (K⁺); anions: chloride (Cl^-), bicarbonate (HCO₃^-)] passes through the pore driven by the effective filtration pressure dP_i. Within the pore, ions interact with the charged walls so that cations are displaced toward the periphery of the wall in a different fashion than are anions (determined by the local zeta potential, ζ). The convective flow with the velocity (v) is not constant across the diameter of the pore (arrows) so that cations and anions will move across the pore with different velocities, resulting in the generation of a filtration-dependent potential. As the physical interactions within the pore are too complex to be calculated, in the isolated perfused Necturus kidney, we determined that the sum of the effects generates a potential of about −0.045 mV per 10 cm H₂O within Bowman’s space [23]. c Necturus maculosus (common mudpuppy). Note that the animal has external gills (arrowhead) as well as primitive lungs

Fig. 3

Forces that influence the passage of albumin across the glomerular filtration barrier. Albumin (alb) is driven across the glomerular filter into the primary urine by convection (i.e. drag of the water) and diffusion (i.e. concentration difference between plasma and primary filtrate). A potential difference (gray arrows) is established across the filtration barrier by passage of the small ionic plasma components (i.e. dipole water, and small solutes sodium, chloride, etc.), which interact with the charged filter walls of the glomerular filtration barrier. As albumin and most plasma proteins are negatively charged, they are driven by electrophoresis back toward the blood