Glomerular Permselectivity

Objectives

• Definition of Glomerular permselectivity• Molecular Basis• Physiological Significance• Various Hypothesis

Classic Definition

Restriction of permeation of macromolecules across a glomerular capillary wall on the basis of molecular size, charge, and physical configuration.

Molecular Basis of Permselectivity

Hypothesis for Permselectivity?

• Glomerular Barrier/ Glomerular Filtration Membrane

1. Charge Selectivity2. Size Selectivity

Charge Selectivity

In acquired and chemically induced kidney disease, albuminuria is the result of dysfunction in proximal tubular cell processing of albumin rather than alterations in

glomerular permeability.

• Sieving Coefficient: Albumin concentration in Bowman’s capsule/albumin concentration in plasma. Describes the transport of a solute across the GFB in relation to that of a freely filtered solute.

Other Supportive StudiesChen S, Wassenhove-McCarthy DJ, Yamaguchi Y, et al. Loss of heparan sulfate glycosaminoglycan assembly in podocytes does not lead to proteinuria. Kidney Int 2008; 74:289–299. (Mice)

Harvey SJ, Jarad G, Cunningham J, et al. Disruption of glomerular basement membrane charge through podocyte-specific mutation of agrin does not alter glomerular permselectivity. Am J Pathol 2007; 171:139–152.

Van den Born J, Pisa B, Bakker MA, et al. No change in glomerular heparan sulfate structure in early human and experimental diabetic nephropathy. J Biol Chem 2006; 281:29606–29613.

Van den Hoven MJ, Wijnhoven TJ, Li JP, et al. Reduction of anionic sites in the glomerular basement membrane by heparanase does not lead to proteinuria. Kidney Int 2008; 73:278–287. (Mice)

Goldberg S, Harvey SJ, Cunningham J, et al. Glomerular filtration is normal in the absence of both agrin and perlecan-heparan sulfate from the glomerular basement membrane. Nephrol Dial Transplant 2009. (Mice)

Size Selectivity

The Albumin Retrieval Hypothesis

Figure 1: The Filtering Glomerulus

Limitations

Why the filter does not clog?

The Electrokinetic Model

• Electrical field (filtration dependent potential or streaming potential) across the GFB (Electrically conductive)

The Pore Model (Two Pore Model/Heteroporous Model)

The Gel Hypothesis

The Gel Permeation Hypothesis

Key Points

• The functioning of the glomerular filter is still not completely understood

• The glomerular filter is an excellent model system for filtering capillaries

• Several models for glomerular filtration have been proposed and have made major contributions to our understanding of glomerular filtration

• A large body of experimental data has been published that is compatible with the notion of a notable streaming potential across the GFB, but more studies are needed

Thank you!

• Dr. Somers

References

• As included