Proteinases and glomerular matrix turnover

The mesangial cell is surrounded by a pericellular matrix (MM), the composition of which helps to determine the physical, mechanical and functional properties of the glomerulus. This highly specialized matrix, like the glomerular basement membrane (GBM), is composed mainly of type IV collagen, laminin and heparan sulphate proteoglycan. In addition, and in contrast to the GBM, the MM also contains significant amounts of fibronectin and chrondroitin sulphate proteoglycan. Under normal physiological conditions these matrix components, as with the components of other connective tissues, are continually being synthesized and degraded, albeit at different rates. In the healthy glomerulus the controlled activity of the mesangial cell is thought to account for both MM synthesis and degradation, and furthermore is involved in the remodelling of the GBM. These processes appear to be tightly regulated since the integrity of both glomerular matrices are strictly maintained in the adult animal. Uncontrolled metabolism of the MM and GBM, however, does occur and a common feature in most forms of chronic renal disease is the development of sclerosis which is particularly marked within the mesangial space. This suggests that in the mesangial cell the mechanisms responsible for the turnover of matrix are no longer coordinated.

Current views suggest that degradation of the extracellular matrix (ECM) is a two step process with initial enzymatic or physical disruption (such as, oxygen radical damage) in the extracellular space followed by endocytosis of the partially degraded components and subsequent digestion by lysosomal proteinases such as cathepsins B, L and D. The serine and the metalloproteinases are most likely to play a critical role in the first stage since they are active at neutral pH and are secreted by cells at the appropriate site. This review summarizes the biochemical properties of tissue proteinases, with particular emphasis on the recent advances of the functional properties and control of the matrix neutral metalloproteinases (MMPs), and indicates their involvement in renal pathology. Since this review is brief and somewhat arbitrarily selective, only recent key papers and reviews are included.