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Complexities of the glomerular basement membrane

Nature Reviews Nephrology volume 17, pages 112–127 (2021)Cite this article

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Abstract

The glomerular basement membrane (GBM) is a key component of the glomerular capillary wall and is essential for kidney filtration. The major components of the GBM include laminins, type IV collagen, nidogens and heparan sulfate proteoglycans. In addition, the GBM harbours a number of other structural and regulatory components and provides a reservoir for growth factors. New technologies have improved our ability to study the composition and assembly of basement membranes. We now know that the GBM is a complex macromolecular structure that undergoes key transitions during glomerular development. Defects in GBM components are associated with a range of hereditary human diseases such as Alport syndrome, which is caused by defects in the genes COL4A3, COL4A4 and COL4A5, and Pierson syndrome, which is caused by variants in LAMB2. In addition, the GBM is affected by acquired autoimmune disorders and metabolic diseases such as diabetes mellitus. Current treatments for diseases associated with GBM involvement aim to reduce intraglomerular pressure and to treat the underlying cause where possible. As our understanding about the maintenance and turnover of the GBM improves, therapies to replace GBM components or to stimulate GBM repair could translate into new therapies for patients with GBM-associated disease.

Key points

  • The glomerular basement membrane (GBM) is composed of many unique components that are likely to be important for appropriate GBM function.

  • The application of new imaging and proteomics technologies is enabling greater insight into GBM organization in health and disease.

  • The composition of the GBM changes during glomerulogenesis to permit proper development and filtration function.

  • The GBM is a major contributor to the size selectivity of the glomerular filter.

  • Causes of GBM-associated disease include primary genetic defects in basement membrane components and damage secondary to autoimmune and metabolic diseases, leading to abnormal synthesis and/or turnover of GBM proteins.

  • Novel pharmacological and genome-editing approaches might facilitate basement membrane repair and treatment of GBM-associated disease.

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Fig. 1: Major components of the GBM.
Fig. 2: Glomerular matrix compartments and transition of basement membrane components during GBM development.
Fig. 3: Major and minor components of the GBM.
Fig. 4: Morphological defects of the glomerular basement membrane associated with disease.
Fig. 5: New technologies to repair defective basement membranes.

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Acknowledgements

This work was supported by a Wellcome Trust Senior Fellowship awarded (202860/Z/16/Z) to R.L. and supporting R.W.N., and by a FAPESP fellowship (2015/03525-2; 2017/26785-5) awarded to M.R.P.T.M.

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Author notes

  1. These authors contributed equally: Richard. W. Naylor, Mychel. R.P.T. Morais.

Authors and Affiliations

  1. Wellcome Centre for Cell-Matrix Research, Division of Cell-Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK

    Richard W. Naylor, Mychel R. P. T. Morais & Rachel Lennon

  2. Laboratory of Reproduction and Extracellular Matrix Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil

    Mychel R. P. T. Morais

  3. Department of Paediatric Nephrology, Royal Manchester Children’s Hospital, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK

    Rachel Lennon

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Glossary

Laminins

A family of glycoproteins that exist as heterotrimers with α, β and γ subunits. Laminin heterotrimers polymerize in the extracellular space to form a sheet that is essential for the formation and function of basement membranes.

Type IV collagen

Encoded for by six genes in vertebrates (COL4A1–COL4A6), type IV collagen provides a scaffold and is present in basement membranes. Type IV collagen proteins form three heterotrimers (α1α1α2, α3α4α5 and α5α5α6) that establish networks in the extracellular space.

Nidogens

Formerly known as entactin, nidogens are dumbbell-shaped proteins found in all basement membranes. Nidogen functions to connect collagens and laminins in the matrix.

Heparan-sulfate proteoglycans

(HSPGs). A large family of extracellular and membrane-attached molecules formed by a major protein that contains one or more covalently attached heparin sulfate glycosaminoglycan chains. Examples of HSPGs in basement membranes include collagen XVIII, agrin and perlecan.

Collagen XVIII

A heparin-sulfate proteoglycan that exists as a homotrimer in basement membranes. It has an important role in maintaining basement membrane integrity by mediating signalling (for example, canonical Wnt signalling) and cell–matrix interactions (such as with integrin and VEGF receptors via a C-terminal endostatin domain).

Plakins

A family of large binding proteins that link cytoskeletal intermediate filaments to other filaments and to junctional complexes such as desmosomes and hemidesmosomes.

Serial block-face SEM

(SBF-SEM). An imaging approach that uses a scanning electron microscope equipped with an automated ultramicrotome that sequentially cuts resin-embedded samples and scans the block surface in a repetitive manner to yield a stack of aligned images with transmission electron microscopy quality. This approach provides volumetric imaging data of tissue structures in the X, Y and Z axes.

Low-vacuum SEM

(LV-SEM). An electron microscopy approach that allows the scanning of non-conductive hydrous samples achieving electron microscopy resolution without prominent charging artefacts.

Helium ion microscopy

An electron microscopy approach in which the beam of electrons used for scanning and surface imaging in conventional SEM is replaced by a focused beam of helium ions to minimize sample damage and obtain high magnification images of uncoated soft specimens with improved sub-nanometre resolution and high surface focus and contrast.

Stimulated emission depletion

(STED). A super resolution microscopy approach that uses a double laser beam to scan multiple fluorescent markers at the same time. The first beam stimulates fluorescence whilst a second creates a light annulus superimposed on top of the first to deplete fluorescence, creating a small scanning beam below the diffraction limit of resolution.

Stochastic optical reconstruction microscopy

(STORM). A super-resolution microscopy approach that uses stochastic photo-switchable fluorescent probes that are activated individually by a weak light source to emit light separately for short time intervals to produce a high-resolution image constructed point-by-point based on the precise location of each individual fluorophore.

Tissue expansion

A sample preparation technique in which a tissue sample embedded within a polymer meshwork (for instance, a hydrogel) is uniformly expanded to enable nanoscale-resolution imaging of preserved tissue structures by immunofluorescence staining and diffraction-limited microscopy.

Haemangioblasts

Multipotent precursor cells that can differentiate into endothelial cells and any cell type within the haematopoietic lineage.

Microcoria

A congenital disorder of the eye characterized by small pupils with a diameter of less than 2 mm.

Advanced glycation end products

(AGEs). Proteins or lipids that are modified by the non-enzymatic binding of a reactive sugar to basic amino acids such as lysine or arginine.

Exon skipping therapy

A technology that can be used to correct the coding reading frame of a mRNA transcript from a mutated gene in order to produce a functional protein.

Joubert syndrome

An inherited ciliopathy caused by mutations in more than 30 genes required for normal ciliary function.

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Naylor, R.W., Morais, M.R.P.T. & Lennon, R. Complexities of the glomerular basement membrane. Nat Rev Nephrol 17, 112–127 (2021). https://doi.org/10.1038/s41581-020-0329-y

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