Abstract
The glomerular basement membrane (GBM) is a specialized structure with a significant role in maintaining the glomerular filtration barrier. This GBM is formed from the fusion of two basement membranes during development and its function in the filtration barrier is achieved by key extracellular matrix components including type IV collagen, laminins, nidogens, and heparan sulfate proteoglycans. The characteristics of specific matrix isoforms such as laminin-521 (α5β2γ1) and the α3α4α5 chain of type IV collagen are essential for the formation of a mature GBM and the restricted tissue distribution of these isoforms makes the GBM a unique structure. Detailed investigation of the GBM has been driven by the identification of inherited abnormalities in matrix proteins and the need to understand pathogenic mechanisms causing severe glomerular disease. A well-described hereditary GBM disease is Alport syndrome, associated with a progressive glomerular disease, hearing loss, and lens defects due to mutations in the genes COL4A3, COL4A4, or COL4A5. Other proteins associated with inherited diseases of the GBM include laminin β2 in Pierson syndrome and LMX1B in nail patella syndrome. The knowledge of these genetic mutations associated with GBM defects has enhanced our understanding of cell–matrix signaling pathways affected in glomerular disease. This review will address current knowledge of GBM-associated abnormalities and related signaling pathways, as well as discussing the advances toward disease-targeted therapies for patients with glomerular disease.
Highlights
The glomerular basement membrane (GBM) is an integral component of the glomerular filtration barrier; an important and highly complex capillary wall that is exposed to mechanical forces driven by capillary hydrostatic pressure
There have been significant research advances in glomerular disease since the early 1990s and the discovery of genetic disease associated with GBM defects and nephrotic syndrome
The exponential discoveries through next-generation sequencing has enabled better understanding of the heterogeneity of GBM disease, which allows the integration of conventional therapies with a more stratified approach to treatment
Summary
Reviewed by: Kimberly Jean Reidy, Children’s Hospital at Montefiore/ Albert Einstein College of Medicine, United States Francois Cachat, University Hospital of Bern, Switzerland Silviu Grisaru, University of Calgary, Canada. The glomerular basement membrane (GBM) is a specialized structure with a significant role in maintaining the glomerular filtration barrier This GBM is formed from the fusion of two basement membranes during development and its function in the filtration barrier is achieved by key extracellular matrix components including type IV collagen, laminins, nidogens, and heparan sulfate proteoglycans. Other proteins associated with inherited diseases of the GBM include laminin β2 in Pierson syndrome and LMX1B in nail patella syndrome. The knowledge of these genetic mutations associated with GBM defects has enhanced our understanding of cell–matrix signaling pathways affected in glomerular disease.
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