Endothelin-1 activates c-Jun NH2-terminal kinase in mesangial cells
Endothelin-1 activates c-Jun NH2-terminal kinase in mesangial cells
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DOI：
10.1038/ki.1997.92
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发表时间：
1997-03-01
影响因子：
19.6
通讯作者：
Kikkawa, R
中科院分区：
文献类型：
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作者：
Araki, S;Haneda, M;Kikkawa, R
已知内皮素-1 (ET-1) 可诱导肾小球系膜细胞的收缩和增殖。 ET-1 已被证明可以通过蛋白激酶 C (PKC) 和蛋白酪氨酸激酶 (PTK) 依赖性途径激活 p42 和 p44 丝裂原激活蛋白激酶 (MAPK)，也称为细胞外信号调节激酶 (ERK)。然而，c-Jun NH2 末端激酶 (JNK)（MAPK 家族成员之一）参与系膜细胞的 ET-1 信号转导尚未阐明。为了澄清这一点，我们研究了ET-1是否可以激活JNK以及培养的系膜细胞中的激活机制。 ET-1以剂量依赖性（最大10(-8)M）和时间依赖性方式增强JNK的活性，在0.15分钟处达到峰值。 ET-1 诱导的 JNK 激活被 ET(A) 受体拮抗剂 BQ-123 阻断。通过佛波醇 12,13 二丁酸酯长期治疗来消耗 PKC 或通过 GF 109203X 抑制 PKC 未能抑制 ET-1 诱导的 JNK 激活。相反，钙螯合（使用 BAPTA/AM 和 EGTA）显着降低 ET-1 诱导的 JNK 激活。此外，离子霉素（一种钙离子载体）和毒胡萝卜素（一种细胞内钙升高剂）能够诱导 JNK 的激活。 ET-1 诱导的 JNK 激活也受到 PTK 抑制剂（除草霉素 A 和金雀异黄酮）的抑制。此外，ET-1 增加了含有 c-Jun 和 c-Fos 蛋白的 AP-1 的 DNA 结合活性。这些结果表明，ET-1能够通过PKC非依赖性和PTK依赖性途径激活肾小球系膜细胞中的JNK，并且细胞内钙对于JNK的激活是必需的。
Endothelin-1 (ET-1) is known to induce the contraction and proliferation of glomerular mesangial cells. ET-1 has been shown to activate p42 and p44 mitogen-activated protein kinases (MAPKs), also known as extracellular signal regulated kinases (ERKs), through both protein kinase C (PKC) and protein tyrosine kinase (PTK)-dependent pathways. However, an involvement of c-Jun NH2-terminal kinase (JNK), one of members of the MAPK family, in ET-1 signaling in mesangial cells has not yet been elucidated. To clarify this point, we examined whether ET-1 could activate JNK and the mechanism of activation in cultured mesangial cells. ET-1 enhanced the activities of JNK in a dose-dependent (10(-8) M maximum) and time-dependent manner, with a peak at .15 minutes. ET-1-induced activation of JNK was blocked by BQ-123, an antagonist for the ET(A) receptor. The depletion of PKC by prolonged treatment with phorbol 12,13 dibutyrate or the inhibition of PKC by GF 109203X failed to inhibit ET-1-induced activation of JNK. In contrast, ET-1-induced activation of JNK was significantly reduced by calcium chelation (with BAPTA/AM and EGTA). In addition, ionomycin, a calcium ionophore, and thapsigargin, an intracellular calcium-rising agent, were able to induce the activation of JNK. ET-1-induced activation of JNK was also inhibited by PTK inhibitors (herbimycin A and genistein). Furthermore, ET-1 increased the DNA-binding activity of AP-1 containing c-Jun and c-Fos proteins. These results indicate that ET-1 is able to activate JNK in glomerular mesangial cells through PKC-independent and PTK-dependent pathways and intracellular calcium is necessary to the activation of JNK.