Revisiting the glomerular charge barrier in the molecular era

The glomerular filtration barrier consists of fenestrated glomerular endothelium, podocyte foot processes/slit diaphragms, and intervening glomerular basement membrane. Its characterization as both a size and charge-selective barrier emerged from studies conducted decades ago. The charge selectivity phenomenon is receiving renewed attention now that the identities and mechanisms of synthesis of relevant molecules are known. Here we summarize studies employing genetic or other in-vivo strategies to investigate glomerular charge.

Attention has focused on glomerular basement membrane heparan sulfate proteoglycans, long considered primary charge barrier components. Agrin contributes significantly to glomerular basement membrane charge but, like perlecan and collagen XVIII, is dispensable for glomerular structure and function. Disruption of glomerular heparan sulfate through transgenic methods or administration of heparanase in vivo provides further evidence against a role for heparan sulfate in glomerular function. Disruption of glomerular sialoproteins, however, causes proteinuria and indicates a critical role for these cell-associated glycoproteins in glomerular filtration.

Recent in-vivo manipulations of glomerular heparan sulfate proteoglycans fail to reveal a crucial role for either them or their anionic charge in glomerular filtration. In contrast, cell-associated sialoproteins are clearly important, but whether their functions actually involve contributions to the charge barrier is unknown.