Calcium channel blockers inhibit proliferation and matrix production in rat mesangial cells: possible mechanism of suppression of AP-1 and CREB activities.
| Autor: | Sugiura T; Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Japan., Imai E, Moriyama T, Horio M, Hori M |
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| Jazyk: | angličtina |
| Zdroj: | Nephron [Nephron] 2000 May; Vol. 85 (1), pp. 71-80. |
| DOI: | 10.1159/000045633 |
| Abstrakt: | Background: Calcium channel blockers (CCBs) are reported to attenuate the loss of renal function in various glomerulonephritides. Methods: To determine the mechanism of action of these drugs, we investigated the effects of CCBs on cell proliferation and extracellular matrix (ECM) production in cultured rat mesangial cells. Results: While stimulation with 5% fetal calf serum (FCS) increased [(3)H]thymidine and [(3)H]proline incorporation into quiescent mesangial cells, incubation with nifedipine and cilnidipine inhibited the increase in a dose-dependent manner. Northern blot analysis demonstrated that 5% FCS increased the expression of transforming growth factor beta (TGF-beta) and fibronectin (FN) mRNA and that CCBs significantly reduced this induction, indicating that CCBs may reduce ECM production through inhibiting TGF-beta and FN. Since activator protein 1 (AP-1) regulates cell proliferation and TGF-beta expression, we evaluated the AP-1 activity by gel mobility shift analysis. Nuclear extracts of FCS-treated cells showed a strong binding to AP-1-specific oligonucleotides which was suppressed by CCBs, suggesting that these agents may inhibit cell proliferation by suppressing AP-1. CCBs also inhibited the binding activity of cyclic adenosine monophosphate responsive element binding protein which regulates FN gene expression. However, neither CCBs nor FCS affected the NFkappaB activity. Conclusion: These results suggest that CCBs may, in part, inhibit the progression of glomerulonephritis through non-hemodynamic actions that include the suppression of mesangial cell proliferation and the production of ECM. (Copyright 2000 S. Karger AG, Basel) |
| Databáze: | MEDLINE |
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