Matrix metalloproteinase inhibitors cause cell cycle arrest and apoptosis in glomerular mesangial cells.
Inflammation is characterized by an excess of cell proliferation often leading to fibrosis and sclerosis with subsequent loss of organ function. We hypothesized that these features may be ameliorated by induction of cell cycle arrest and apoptosis as result of therapy with matrix metalloproteinase (MMP) inhibitors. In our study, mesangial cells and experimental mesangial proliferative glomerulonephritis provided the model of inflammation. First, we investigated the effect of the MMP inhibitor BB-1101 in anti-Thy1.1 nephritis. The numbers of apoptotic glomerular cells in nephritic rats increased about 4 and 6 times as a result of BB-1101 therapy, observed 11 and 14 days after induction of disease, respectively. Subsequently, rat mesangial cells were exposed to an MMP inhibitor in vitro. Fluorescence-activated cell sorter analyses of cells exposed to RO111-3456 demonstrated a dose-dependent cell cycle arrest in the G(0)/G(1) phase associated with increased expression of statin. The cell cycle arrest was followed by apoptosis as investigated by terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) biotin nick-end labeling (TUNEL) and acridine orange/ethidium bromide stainings, as well as by annexin V binding. The induction of p53, p21, and bax, but not the Fas/FasL pathway appeared to play an important pathogenetic role. In summary, MMP inhibitors induce cell cycle arrest followed by apoptosis in mesangial cells. These features help to explain the anti-inflammatory effects of these compounds, such as reduction of mesangial cell proliferation and attenuation of extracellular matrix accumulation. In conclusion, induction of cell cycle arrest with subsequent apoptosis may offer new perspectives in the therapy of inflammation even beyond kidney diseases.
Daniel
C
C
Division of Nephrology and Hypertension, University of Bern, CH-3010 Bern, Switzerland.
Duffield
J
J
Brunner
T
T
Steinmann-Niggli
K
K
Lods
N
N
Marti
H P
HP
D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D001593:Benzyl Compounds; D002453:Cell Cycle / Q000187:drug effects*; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005920:Glomerular Mesangium / Q000187:drug effects* / Q000473:pathology; D005921:Glomerulonephritis / Q000209:etiology; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D010431:Pentoxifylline / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology*; D016271:Proto-Oncogene Proteins c-myc / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D013386:Succinates; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
D017304:Annexin A5; C101468:BB 1101; D001593:Benzyl Compounds; D004338:Drug Combinations; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D013386:Succinates; D016159:Tumor Suppressor Protein p53; D003907:Dexamethasone; D010431:Pentoxifylline