The role of matrix metalloproteinases in the activation of mesangial cells.
Mesangial cells play a prominent role in renal inflammatory disorders, especially in IgA nephropathy. This disease represents the most common form of glomerulonephritis that eventually leads to progressive kidney failure requiring renal replacement therapy. In kidney transplants, IgA nephropathy displays a high recurrence rate in the order of 50%. Increased cell proliferation rates and extracellular matrix (ECM) accumulation are crucial targets in the therapy of glomerulonephritis, including IgA nephropathy. The active role of matrix metalloproteinases (MMP) in the regulation of these two features is rapidly emerging. We studied a model of a specific type of mesangial cell-mediated glomerular inflammation, such as experimental mesangial proliferative glomerulonephritis and cultured proliferating mesangial cells. In addition, these tools allowed us to evaluate a new therapeutic strategy based on MMP inhibition. Inhibition of MMP activity and synthesis by antisense technology and by a synthetic inhibitor in vitro, successfully reverted the inflammatory mesangial cell phenotype to the physiologically existing resting state. In vivo, a hydramate-based MMP inhibitor attenuated excess mesangial cell proliferation and ECM accumulation in anti-Thy1.1 nephritis. The anti-proliferative effect was achieved by the induction of cell cycle arrest followed by apoptosis, mediated by the induction of p53, p21 and bax, but not by the Fas/FasL pathway. In conclusion, MMP inhibitors provide a new approach to the therapy of inflammation probably even beyond the field of renal disorders.
Division of Nephrology/Hypertension, Inselspital Bern, Switzerland. hmarti@insel.ch
Hans-Peter
HP
Marti
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D005920:Glomerular Mesangium / Q000166:cytology* / Q000201:enzymology; D005921:Glomerulonephritis / Q000188:drug therapy; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000145:classification / Q000502:physiology*; D011480:Protease Inhibitors / Q000627:therapeutic use
D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D020782:Matrix Metalloproteinases