The glomerular basement membrane as a barrier to albumin

Abstract

The glomerular basement membrane (GBM) is the central, non-cellular layer of the glomerular filtration barrier that is situated between the two cellular components--fenestrated endothelial cells and interdigitated podocyte foot processes. The GBM is composed primarily of four types of extracellular matrix macromolecule--laminin-521, type IV collagen α3α4α5, the heparan sulphate proteoglycan agrin, and nidogen--which produce an interwoven meshwork thought to impart both size-selective and charge-selective properties. Although the composition and biochemical nature of the GBM have been known for a long time, the functional importance of the GBM versus that of podocytes and endothelial cells for establishing the glomerular filtration barrier to albumin is still debated. Together with findings from genetic studies in mice, the discoveries of four human mutations affecting GBM components in two inherited kidney disorders, Alport syndrome and Pierson syndrome, support essential roles for the GBM in glomerular permselectivity. Here, we explain in detail the proposed mechanisms whereby the GBM can serve as the major albumin barrier and discuss possible approaches to circumvent GBM defects associated with loss of permselectivity.

Figure 1. The components of glomerular basement membrane (GBM) and known alterations in Pierson and Alport syndromes

(A) The normal GBM is composed of laminin-521 (α5β2γ1), type IV collagen α3α4α5, nidogen and heparan sulfate proteoglycan (HSPG; primarily agrin). Podocytes and endothelial cells each contribute at least a subset of these components to the GBM (arrows; see text for details). Most of the plasma albumin (black dots) is restricted to the capillary lumen. FP, foot processes. (B and C) Mutations in two GBM components result in albuminuria both in human patients and in mouse models. (B) The GBM of Lamb2 knockout mice lacks laminin-521 and instead contains ectopic laminins (shown in dark gray text), such as laminin-111, -211, -332, and -511. However, the laminin network made of these ectopic laminins is defective, leading to increased passage of plasma protein across the barrier. At 1 week, Lamb2 mutant mice have proteinuria due to the defective GBM, but without podocyte foot process effacement. At 2 weeks, podocyte abnormalities can be detected, followed by increasing proteinuria and widespread effacement. These results indicate that proteinuria precedes podocyte abnormalities in Lamb2 mutant mice, highlighting the importance of the GBM as a barrier to plasma protein. (C) The GBM of Col4a3 mutant mice lacks the collagen α3α4α5(IV) network. Although there is increased deposition of collagen α1α1α2(IV) as a compensatory mechanism, the resulting GBM becomes split and thickened and accumulates multiple ectopic laminins (shown in dark gray text). Eventually there is increased loss of plasma protein across the filtration barrier and proteinuria.