Angiotensin II induces thrombospondin-1 production in human mesangial cells via p38 MAPK and JNK:: a mechanism for activation of latent TGF-β1
Angiotensin II induces thrombospondin-1 production in human mesangial cells via p38 MAPK and JNK:: a mechanism for activation of latent TGF-β1
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DOI：
10.1152/ajprenal.00139.2003
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发表时间：
2004-02-01
影响因子：
4.2
通讯作者：
Kohno, N
中科院分区：
文献类型：
--
作者：
Naito, T;Masaki, T;Kohno, N
血管紧张素II诱导肾小球系膜细胞分泌和激活转化生长因子-β（TGF-β）。然而，运作这一机制的机制尚不清楚。血小板反应蛋白-1（TSP-1）由受损肾小球中的系膜细胞产生，是已知激活潜伏的TGF-β（1）复合物的几种分子之一。因此，我们研究了ANG II诱导的人系膜细胞（HMC）中潜伏性TGF-β（1）的激活是否通过TSP-1起作用。加入ANG II（1 - 100 nM）的HMC显着增加TSP-1 mRNA在6小时内，随后TSP-1蛋白的生产增加，如细胞的Western印迹分析和培养上清液的免疫测定所示。ANG II诱导的TSP-1 mRNA和蛋白的产生被ANG II 1型（AT（1））受体拮抗剂完全抑制，但不受AT（2）受体拮抗剂的影响。TSP-1特异性阻断肽的使用表明ANG II诱导的潜伏性TGF-β 1的激活通过TSP-1起作用。接下来，我们研究了ERK 1/2、p38 MAPK和JNK在ANG II诱导的HMC产生TSP-1中的作用。上游ERK 1/2抑制剂PD-98059的加入不影响ANG II诱导的TSP-1产生，而p38 MAPK抑制剂SB-203580或JNK抑制剂SP-600125的加入显著降低TSP-1产生。总之，这项研究表明，ANG II诱导的HMC中潜伏TGF-β 1的激活通过TSP-1起作用。此外，ANG II诱导的TSP-1产生依赖于p38 MAPK和JNK信号传导。
ANG II induces secretion and activation of transforming growth factor-beta (TGF-beta) by glomerular mesangial cells. However, the mechanisms that operate this are unclear. Thrombospondin-1 (TSP-1), which is produced by mesangial cells in damaged glomeruli, is one of several molecules known to activate the latent TGF-beta(1) complex. Therefore, we examined whether the ANG II-induced activation of latent TGF-beta(1) in human mesangial cells (HMC) operates via TSP-1. The addition of ANG II (1 - 100 nM) to HMC significantly increased TSP-1 mRNA within 6 h, followed by an increase in TSP-1 protein production as shown by Western blot analysis of cells and immunoassay of the culture supernatant. Production of ANG II-induced TSP-1 mRNA and protein was completely inhibited by an ANG II type 1 (AT(1))-receptor antagonist but was unaffected by an AT(2)-receptor antagonist. Use of a TSP-1-specific blocking peptide demonstrated that the ANG II-induced activation of latent TGF-beta(1) operates via TSP-1. Next, we investigated the role of ERK1/2, p38 MAPK, and JNK in ANG II-induced TSP-1 production in HMC. The addition of the upstream ERK1/2 inhibitor PD-98059 did not affect ANG II-induced TSP-1 production, whereas addition of either the p38 MAPK inhibitor SB-203580 or the JNK inhibitor SP-600125 significantly reduced TSP-1 production. In conclusion, this study has demonstrated that ANG II-induced activation of latent TGF-beta(1) in HMC operates via TSP-1. Furthermore, ANG II-induced TSP-1 production is dependent on p38 MAPK and JNK signaling.