Complexities of the glomerular basement membrane

Abstract

The glomerular basement membrane (GBM) is a key component of the glomerular capillary wall and is essential for kidney filtration. Major components of the GBM include laminins, collagen IV, nidogens and heparan sulphate 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 disease such as diabetes mellitus. Current treatment for diseases associated with GBM involvement aims 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.

The underestimated burden of monogenic kidney disease in adults waitlisted for kidney transplantation

“…Of the overall eight patients with COL4related disease only two of these individuals showed any extrarenal manifestation, but none of the patients displayed the full clinical picture described for Alport syndrome. The high proportion of COL4-related disease is in accordance with current literature findings that describe variants in COL4A3-5 genes as the second most frequent genetic kidney disease 18,19 .…”

Collagen IVα345 dysfunction in glomerular basement membrane diseases. II. Crystal structure of the α345 hexamer

“…Prominent diseases of the glomerular basement membrane (GBM), a specialized form of the extracellular matrix, are diabetic nephropathy (DN), Alport syndrome (AS), and Goodpasture’s disease (GP). The morphological abnormalities in the GBM involve structural alterations in collagen IV α345 scaffold, the major GBM component ( 1 , 2 , 3 ). The mechanisms whereby collagen IV enables normal GBM function or causes GBM abnormalities and dysfunction in disease are unknown.…”

Early Diabetes Aggravates Renal Ischemia/reperfusion-induced Acute Kidney Injury 

“…In contrast, renal IR resulted in an increase in collagen IV gene expression, suggesting a compensatory mechanism of GBM against the possible loss of its components. Collagen IV is the main component of GBM, and its function is to provide structure and support for other cell types, such as podocytes [57].…”

“…However, compared with nondiabetic mice subjected to renal IR, mice with early diabetes subjected to renal IR exhibited moderate collagen I and III gene expression. Interestingly, it is known that matrix metalloproteinases (MMPs), such as MMP-2 and MMP-9, are upregulated in diabetic kidneys (57). MMPs are proteases involved in the turnover of extracellular matrix and degradation of bioactive proteins, including collagen (19).…”