Rapamycin at subimmunosuppressive levels inhibits mesangial cell proliferation and extracellular matrix production
Rapamycin at subimmunosuppressive levels inhibits mesangial cell proliferation and extracellular matrix production
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DOI：
10.1152/ajprenal.00128.2006
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发表时间：
2007-01-01
影响因子：
4.2
通讯作者：
Robson, Michael G.
中科院分区：
文献类型：
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作者：
Lock, Helen R.;Sacks, Steven H.;Robson, Michael G.
鉴于其已被证实的抗增殖作用，雷帕霉素提供了治疗系膜增生性疾病的潜力。先前的数据显示了高剂量雷帕霉素对系膜细胞增殖的影响，但尚未探讨其作用机制。因此，我们探讨了低水平雷帕霉素对系膜细胞增殖的影响及其作用机制。小鼠系膜细胞的原代培养物在含有不同浓度雷帕霉素的血清的培养基中生长。0.1 ng/ml的雷帕霉素浓度导致细胞数量和DNA合成减少，对细胞凋亡没有影响。IV型胶原蛋白的产生在0.01 ng/ml雷帕霉素时受到抑制，尽管基因表达不受影响。P70 S6 K磷酸化以剂量依赖性方式与对细胞数量和DNA合成的影响平行地被抑制，但在0.01 ng/ml雷帕霉素下没有观察到影响。这些数据显示0.1ng/ml雷帕霉素对系膜细胞增殖和p70 S6激酶磷酸化的影响以及0.01ng/ml雷帕霉素对胶原IV产生的影响。我们建议进一步的体内研究应探讨低剂量雷帕霉素治疗系膜增生性肾小球肾炎的潜力。
In view of its proven antiproliferative effects, rapamycin offers potential in the treatment of mesangioproliferative disease. Previous data have shown an effect of rapamycin on mesangial cell proliferation at high doses and have not explored the mechanism of action. Therefore, we explored the effects and mechanism of action of low levels of rapamycin on mesangial cell proliferation. Primary cultures of mouse mesangial cells were grown in medium containing serum with differing concentrations of rapamycin. A rapamycin concentration of 0.1 ng/ml caused a decrease in cell number and DNA synthesis with no effect on apoptosis. Type IV collagen protein production was inhibited at 0.01 ng/ml rapamycin, although gene expression was unaffected. P70S6K phosphorylation was inhibited in parallel with the effects on cell number and DNA synthesis in a dose-dependent manner, but no effect was seen at 0.01 ng/ml rapamycin. These data show an effect on mesangial cell proliferation and p70S6 kinase phosphorylation of 0.1 ng/ml rapamycin and an effect on collagen IV production of 0.01 ng/ml rapamycin. We suggest that further in vivo studies should explore the potential for low-dose rapamycin in the treatment of mesangioproliferative glomerulonephritis.