Recent insights into the structure and functions of heparan sulfate proteoglycans in the human glomerular basement membrane

As the first barrier to be crossed on the way to urinary space, the glomerular basement membrane (GBM) plays a key role in renal function. The permeability of the GEM for a given molecule is highly dependent on its size, shape and charge. As early as 1980, the charge-selective permeability was demonstrated to relate to the electrostatic properties of covalently bound heparan sulfates (HS) within the GEM. Since the identification of perlecan as a heparan sulfate proteoglycan (HSPG) of basement membranes, the hypothesis that perlecan could be a crucial determinant of GEM permselectivity received considerable attention. In addition to perlecan, the GEM also contains other HSPG species, one of which was identified as agrin. The high local expression of agrin in the GEM, together with the presence of agrin receptors at the cell-matrix interface, suggests that this HSPG contributes to glomerular function in multiple ways. Here, we review the current knowledge regarding the structure and functions of HSPGs in the GEM, and discuss how these molecules could be involved in various glomerular diseases. Possible directions for future investigation are suggested.