The glomerular basement membrane

Abstract

The kidney's glomerular filtration barrier consists of two cells-podocytes and endothelial cells-and the glomerular basement membrane (GBM), a specialized extracellular matrix that lies between them. Like all basement membranes, the GBM consists mainly of laminin, type IV collagen, nidogen, and heparan sulfate proteoglycan. However, the GBM is unusually thick and contains particular members of these general protein families, including laminin-521, collagen α3α4α5(IV), and agrin. Knockout studies in mice and genetic findings in humans show that the laminin and type IV collagen components are particularly important for GBM structure and function, as laminin or collagen IV gene mutations cause filtration defects and renal disease of varying severities, depending on the nature of the mutations. These studies suggest that the GBM plays a crucial role in establishing and maintaining the glomerular filtration barrier.

Figure 1

Ultrastructure of a typical glomerular capillary loop. A red blood cell (RBC) is present in the capillary lumen, which is lined by an endothelial cell with fenestrations (black arrowheads). The glomerular basement membrane (GBM) is a ribbon-like extracellular matrix that lies between the endothelium and the podocyte foot processes (FPs). The mesangium contains mesangial cells and their associated matrix. A parietal epithelial cell (PEC) is visible lining Bowman’s capsule.

Figure 2

The major components of basement membranes: laminin, type IV collagen, nidogen, and heparan sulfate proteoglycan (agrin is shown due to its prevalence in the GBM, though perlecan is more widely found in basement membranes). Collagen IV is a triple helical protein with C-terminal noncollagenous domains (NC1) and N-terminal 7S domains; these are important in network formation. Laminin α, β, and γ chains assemble with each other via the laminin coiled-coil (LCC) domain. Laminin N-terminal (LN) domains are involved in polymerization of trimers, which initiates basement membrane formation. The C-terminal laminin globular (LG) domain contains binding sites for cell surface receptors. Agrin, a modular protein containing glycosaminoglycan (GAG) side chains, binds to the laminin long arm via the γ1 chain, whereas nidogen binds to the short arm of laminin γ1 as well as to collagen IV.

Figure 3

GBM lesions in a mouse model of Alport syndrome (hereditary nephritis). The mouse is homozygous for a null mutation in Col4a3 and therefore lacks the collagen α3α4α5(IV) network. Note the outpocketings of the GBM (asterisks) that project toward the podocyte, which has lost much of the normal foot process architecture.

Figure 4

Detection of a GBM charge defect in a podocyte-specific agrin mutant mouse using the cationic probe polyethyleneimine to detect anionic sites. In the control, discrete subepithelial anionic sites are revealed (A), but these are significantly reduced in the mutant (B). Despite this reduction in anionic charge, mutants displayed no detectable filtration barrier defects.