Alport syndrome and Pierson syndrome: Diseases of the glomerular basement membrane

Abstract

The glomerular basement membrane (GBM) is an important component of the kidney's glomerular filtration barrier. Like all basement membranes, the GBM contains type IV collagen, laminin, nidogen, and heparan sulfate proteoglycan. It is flanked by the podocytes and glomerular endothelial cells that both synthesize it and adhere to it. Mutations that affect the GBM's collagen α3α4α5(IV) components cause Alport syndrome (kidney disease with variable ear and eye defects) and its variants, including thin basement membrane nephropathy. Mutations in LAMB2 that impact the synthesis or function of laminin α5β2γ1 (LM-521) cause Pierson syndrome (congenital nephrotic syndrome with eye and neurological defects) and its less severe variants, including isolated congenital nephrotic syndrome. The very different types of kidney diseases that result from mutations in collagen IV vs. laminin are likely due to very different pathogenic mechanisms. A better understanding of these mechanisms should lead to targeted therapeutic approaches that can help people with these rare but important diseases.

Fig. 1. Transmission electron micrograph showing the structure of a typical glomerular capillary from an adult mouse

The glomerular basement membrane (GBM) is flanked by podocyte foot processes (FPs, asterisks) and the fenestrated glomerular endothelium (Endo). FPs emanate from podocyte cell bodies. Red blood cells (RBCs) can be seen in the lumen of the capillary.

Fig. 2. Schematic diagrams of the four major GBM components

Four type IV collagen α3α4α5(IV) triple helical heterotrimers (or protomers) interact via their 7S domains, and two interact via their NC1 domains to form the collagen IV network. LM-521 heterotrimers interact with each other via their laminin N-terminal (LN) domains to form a separate network. Nidogen binds to both collagen IV and laminin networks to help stabilize them and the GBM by linking them to each other. Agrin binds to LM-521 via its N-terminal agrin (NtA) domain. Both agrin and laminin α5 have C-terminal laminin globular (LG) domains that serve as ligands for cell surface receptors. These interactions link the GBM to the cell surface and allows the cell to influence the organization of GBM components.

Fig. 3. Transmission electron microscopy demonstrates splitting and thickening of the GBM in the Col4a3−/− mouse model of Alport syndrome

A. Early stage of pathology shows mild GBM splitting and thickening (asterisk) with preserved podocyte foot processes (arrows) and endothelial cell fenestrations (arrowheads). B. Later stage of pathology shows extensive GBM splitting and thickening (black asterisk) and effacement of podocyte foot processes (arrows). Endothelial cell fenestrations appear to be maintained (arrowheads), and there is evidence of podocyte invasion into the GBM towards the endothelium (white asterisks). Some of these processes appear embedded in the GBM due to the plane of section.

Fig. 4. Ultrastructural analysis of glomerular capillary walls in control and Lamb2 mutant kidneys that model Pierson syndrome

A. Lamb2+/− control mouse shows typical podocyte foot processes and endothelial fenestrations adjacent to the GBM. B. A Lamb2−/− mouse shows effaced or broadened podocyte foot processes but retained endothelial cell fenestrations and a GBM of normal appearance. C. A Lamb2−/− mouse was injected intravenously on consecutive days with LM-521. This treatment attenuated podocyte foot process effacement and delayed the onset of high level proteinuria. Arrows, podocyte foot processes; arrowheads, endothelial cell fenestrations; asterisks, GBM.