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Matrix metalloproteinase inhibitors cause cell cycle arrest and apoptosis in glomerular mesangial cells
C Daniel1, J Duffield, T Brunner
1Division of Nephrology and Hypertension, University of Bern, CH-3010 Bern, Switzerland.
Abstract:
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.
Insights
Matrix metalloproteinase (MMP) inhibitors can reduce inflammation by inducing cell cycle arrest and apoptosis in mesangial cells. This therapeutic approach shows promise for treating inflammatory diseases, including kidney conditions.
Area of Science:
- Nephrology
- Cell Biology
- Pharmacology
Background:
- Inflammation involves excessive cell proliferation, leading to fibrosis, sclerosis, and organ dysfunction.
- Matrix metalloproteinase (MMP) inhibitors are explored for their potential to ameliorate these inflammatory features.
Purpose of the Study:
- To investigate the therapeutic effects of MMP inhibitors on mesangial cells and experimental glomerulonephritis.
- To determine if MMP inhibitors can induce cell cycle arrest and apoptosis in inflammatory conditions.
Main Methods:
- In vivo study using BB-1101 in anti-Thy1.1 nephritis rat model.
- In vitro study exposing rat mesangial cells to MMP inhibitor RO111-3456.
- Flow cytometry, TUNEL, acridine orange/ethidium bromide, and annexin V binding assays were used to assess cell cycle arrest and apoptosis.
Main Results:
- BB-1101 therapy significantly increased glomerular cell apoptosis in nephritic rats.
- RO111-3456 induced dose-dependent cell cycle arrest in the G(0)/G(1) phase and increased statin expression.
- Cell cycle arrest was followed by apoptosis, involving p53, p21, and bax induction.
Conclusions:
- MMP inhibitors effectively induce cell cycle arrest and subsequent apoptosis in mesangial cells.
- These mechanisms explain the anti-inflammatory effects of MMP inhibitors, reducing cell proliferation and matrix accumulation.
- MMP inhibitor-induced apoptosis offers potential therapeutic strategies for inflammatory diseases beyond kidney disorders.