New strategy to treat glomerular inflammation by inhibition of mesangial cell matrix metalloproteinases.
Therapy of inflammation often requires the attenuation of excess cell proliferation and of extracellular matrix (ECM) accumulation. It is increasingly recognised that matrix metalloproteinases (MMP) play an important role in the regulation of these two features. For our studies, experimental mesangial proliferative glomerulonephritis and cultured mesangial cells provided the inflammation model and the opportunity to evaluate a new therapeutic strategy based on MMP inhibition. In vitro inhibition of MMP activity and synthesis successfully returned the inflammatory mesangial cell phenotype to the normally occurring resting state. In vivo, excess mesangial cell proliferation and ECM accumulation in experimental mesangial proliferative glomerulonephritis were significantly ameliorated by the use of a synthetic MMP inhibitor. Interestingly, these inhibitors lead to increased mesangial cell apoptosis. In conclusion, the antiproliferative effect of MMP inhibitors opens new perspectives in the therapy of inflammation, probably even beyond the scope of kidney diseases.
Marti
H P
HP
Abteilung Nephrologie/Hypertonie, Inselspital, Berne. hmarti@insel.ch
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001593:Benzyl Compounds; D002455:Cell Division / Q000187:drug effects*; D046508:Culture Techniques; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005920:Glomerular Mesangium / Q000187:drug effects*; D015432:Glomerulonephritis, Membranoproliferative / Q000201:enzymology*; D006801:Humans; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D010431:Pentoxifylline / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013386:Succinates
C101468:BB 1101; D001593:Benzyl Compounds; D004338:Drug Combinations; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; C097661:Ro 31-9790; D013386:Succinates; D003907:Dexamethasone; D010431:Pentoxifylline