The basement membrane, or basal lamina, is a specialized extracellular matrix (ECM) that underlies epithelial and endothelial cells and surrounds adipocytes, peripheral nerves, and muscle.  There are five main components that make up all basement membranes: type IV collagen (collagen IV), laminin, nidogens, perlecan, and fibronectin.  The functions of the basement membrane are to provide structural integrity and polarity to overlying cells, while also physically influencing cell behavior.  It does this by serving as an adhesive substrate for cells to bind, functioning as filtration barriers, and regulating cell growth and differentiation.

Collagen IV is the most abundant and widely distributed component of the basement membrane and contributes to 50% of basement membrane composition.  Collagen IV specifically binds platelets, hepatocytes, keratinocytes, endothelial cells, and tumor cells.

Collagen IV is comprised of six distinct collagen IV chains, COL4A1-COL4A6 (also written as a1(IV)-a6(IV)).  The chains assemble into heterotrimeric isoforms that form strong scaffolds together with laminins, nidogen, and perlecan.  COL4A1 and COL4A2 are the most prevalent collagen IV chains and are ubiquitously expressed in nearly all epithelial basement membranes, but are also the only Col IV chains found in the liver.  The remaining COL4A3-COL4A6 chains are distributed in a tissue-specific manner with  COL4A3, COL4A4, and COL4A5 being found in the kidney, lung, and neuromuscular junctions and  COL4A5 and COL4A6 are expressed in smooth muscles and at neuromuscular junctions.

It is important to note that all collagen IV a-chains contain an N-terminal 7S domain, a triple helix collagenous domain, and a C-terminal non-collagenous domain (NCl domain).   Serum and urinary levels of the 7S domain and NCI domain are thought to indicate basement membrane degradation, whereas measurements containing the helical region are considered to represent basement membrane formation.

Collagen IV- Fibrosis Biomarker

Kidney Fibrosis

The capillary vessels of the kidney glomeruli are particularly sensitive to changes in collagen IV levels and haemodynamic states. Glomerulonephritis occurs when the filtering component of the kidney, the glomerulus, becomes injured.  Injury to the glomerulus can drive fibrosis and the accumulation of collagen IV. Diabetic nephropathy is characterized by high blood glucose levels that lead to nephron damage.  Elevated urinary collagen IV levels in diabetic individuals correlate to glomerular fibrosis.  Chronic kidney diseases, including chronic transplant nephropathy, may exhibit altered collagen IV levels, indicating that collagen IV turnover in the basement membrane is affected following kidney damage.  Injury to the liver and kidney elicits a pro-fibrotic response that releases collagen IV, making collagen IV an interesting biomarker to consider while investigating liver and kidney fibrosis and damage.