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The glomerular basement membrane as a barrier to albumin

Nature Reviews Nephrology volume 9, pages 470–477 (2013)Cite this article

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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.

Key Points

  • The glomerular basement membrane (GBM) is the extracellular matrix component of the glomerular filtration barrier; it is flanked by the podocyte and glomerular endothelial cell layers

  • The major GBM components are laminin-521, type IV collagen α3α4α5, nidogen, and the heparan sulphate proteoglycan agrin

  • Mutations in COL4 genes that result in absence of the type IV collagen α3α4α5 network cause Alport syndrome, a hereditary nephritis accompanied by hearing defects

  • Mutations in laminin β2 (LAMB2) cause Pierson syndrome, a congenital nephrotic syndrome with associated eye and neurologic abnormalities

  • Studies using mouse models of Pierson and Alport syndromes have shown that the defective GBM is more permeable to macromolecules than is the normal GBM, suggesting that it has a role in permselectivity

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Figure 1: The components of the GBM.
Figure 2: Mutations in Lamb2 result in albuminuria in a mouse model of Pierson syndrome.
Figure 3: Mutations in the genes encoding type IV collagen α3, α4, or α5 result in albuminuria in a mouse model of Alport syndrome.

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Acknowledgements

The authors are supported by NIH grants R01DK078314, R21DK095419, and P30DK079333 and by a grant from the Alport Syndrome Foundation. J. H. Suh is also supported by NIH training grant T32DK007126.

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  1. Renal Division, Department of Internal Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, 63110, MO, USA

    Jung Hee Suh & Jeffrey H. Miner

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Suh, J., Miner, J. The glomerular basement membrane as a barrier to albumin. Nat Rev Nephrol 9, 470–477 (2013). https://doi.org/10.1038/nrneph.2013.109

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