Unraveling the Mechanisms of Glomerular Ultrafiltration

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Abstract
It is well established that the glomerular filtration barrier behaves as a size-selective filter that restricts the passage of plasma macromolecules based on their size, shape, and charge (1,2,3). Negatively charged molecules are filtered in smaller amounts than neutral molecules of comparable size, and the traversal of positively charged molecules is actually facilitated. The exact locations of the filtration functions within the barrier have been a matter of debate. Farquhar and coworkers demonstrated the presence of anionic sites in the GBM (4,5) and proposed that they contain heparan sulfate (6). The GBM is a molecular scaffold composed of tightly cross-linked type IV collagen, laminin, nidogen, and proteoglycans (7,8). Type IV collagen and laminin form two apparently independent structural networks that are linked through nidogen. In addition to providing strength to the GBM, type IV collagen and laminin probably also have adhesion roles for the endothelial cells and podocytes. The basement membrane-specific heparan sulfate proteoglycans perlecan (9) and agrin (10) are components of the GBM. After perfusion of kidneys with heparinase, which removes all glycosaminoglycans except keratan sulfate, Kanwar et al. (11) showed increased permeability of the GBM to ferritin (molecular weight, 470 kD), and Caulfield and Farquhar (12) have also shown loss of anionic sites from the GBM in aminonucleoside nephrosis. These and similar data from other laboratories support the role of negative glycosaminoglycans as an anionic filtration barrier.

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