Basement Membrane Defects in Genetic Kidney Diseases

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.

Keywords: Alport syndrome; Pierson syndrome; basement membrane; collagen IV; genetic variation; glomerulus.

Figure 1

Cross-section image of normal glomerulus showing cellular and extracellular matrix compartments. Abbreviation: GBM, glomerular basement membrane.

Figure 2

Interaction between components of the glomerular basement membrane and adjacent glomerular cells. Abbreviations: AGT II, angiotensin-II; AKT, protein kinase B; aPKC, atypical protein kinase C; AT1, angiotensin-I; CD2AP, CD2-associated protein; DAG, diacylglycerol; ER, endoplasmic reticulum; FAK, focal adhesion kinase; IQGAP-1, IQ motif containing GTPase-activating protein-1; ILK, integrin-linked kinase; IP3, inositol triphosphate; MYH9, myosin heavy chain 9; MYO1E, myosin-1E; PIP3, phosphatidylinositol 4,5-biphosphate; Nck1, non-catalytic region of tyrosine kinase adaptor protein-1; NHERF1/2, Na⁺/H⁺ exchanger regulatory factor-1/2; PI3K, phosphoinositide 3-kinase; PINCH, Cys-His-rich protein; PKC, protein kinase C; PLC, phosphatidylinositol phospholipase C; TRPC6, transient receptor potential cation channel-6; WASP, Wiskott–Aldrich syndrome protein.

Figure 3

Type IV collagen network formation involving interaction between the α-chains through their NC1 domains to form a dimer or through their 7S domains to produce a tetramer. These complex interactions are important for the development of the type IV collagen scaffold, which are subsequently reinforced by suprastructural associations of collagenous domains.

Figure 4

Interactions between laminin and other extracellular matrix components in the glomerular basement membrane. Abbreviations: LF, globular F terminal domain; LG, globular C terminal domain; LN, globular N terminal domain.