Angiotensin II-induced ERK1/ERK2 activation and protein synthesis are redox-dependent in glomerular mesangial cells
Angiotensin II-induced ERK1/ERK2 activation and protein synthesis are redox-dependent in glomerular mesangial cells
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DOI：
10.1042/bj20031614
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发表时间：
2004-07-01
影响因子：
4.1
通讯作者：
Abboud, HE
中科院分区：
文献类型：
--
作者：
Gorin, Y;Ricono, JM;Abboud, HE
血管紧张素II(Ang II)刺激肾小球系膜细胞肥大。Ang II发挥这种作用的信号机制尚不清楚。Ang II下游的潜在靶点是细胞外信号调节蛋白1和2(ERK1/ERK2)。我们证明Ang II通过AT受体激活ERK1/ERK2。花生四烯酸(AA)模拟Ang II对ERK1/ERK2的作用，磷脂酶A(2)抑制剂可阻断Ang II诱导的ERK1/ERK2激活。抗氧化剂N-乙酰半胱氨酸以及NAD(P)H氧化酶抑制剂二苯基碘和氧化苯砷可阻断Ang II和AA诱导的ERK1/ERK2激活。此外，显性负性rac1(N17rac1)阻断ERK1/ERK2对Ang II和AA的激活，而结构性激活的rac1导致ERK1/ERK2活性增加。NOX4 NAD(P)H氧化酶反义寡核苷酸显著降低Ang II和AA对ERK1/ERK2的激活。我们还发现，N17rac1或MEK(丝裂原活化蛋白激酶/ERK激酶)抑制剂可抑制Ang II和AA诱导的蛋白质合成。这些结果表明，Ang II通过AA和NOX4产生的活性氧刺激ERK1/ERK2，提示这些分子在连接Ang II受体AT和ERK1/ERK2激活的信号通路中起Ang II下游信号转导的作用。这一涉及AA、rac1、NOX4、活性氧和ERK1/ERK2的信号通路可能在Ang II诱导的系膜细胞肥大中起重要作用。
Angiotensin II (Ang II) stimulates hypertrophy of glomerular mesangial cells. The signalling mechanism by which Ang II exerts this effect is not precisely known. Downstream potential targets of Ang II are the extracellular-signal-regulated kinases 1 and 2 (ERK1/ERK2). We demonstrate that Ang II activates ERK1/ERK2 via the AT, receptor. Arachidonic acid (AA) mimics the action of Ang II on ERK1/ERK2 and phospholipase A(2) inhibitors blocked Ang II-induced ERK1/ERK2 activation. The antioxidant N-acetylcysteine as well as the NAD(P)H oxidase inhibitors diphenylene iodonium and phenylarsine oxide abolished both Ang II- and AA-induced ERK1/ERK2 activation. Moreover, dominant-negative Rac1 (N17Rac1) blocks activation of ERK1/ERK2 in response to Ang II and AA, whereas constitutively active Rac1 resulted in an increase in ERK1/ERK2 activity. Antisense oligonucleotides for Nox4 NAD(P)H oxidase significantly reduce activation of ERK1/ERK2 by Ang II and AA. We also show that protein synthesis in response to Ang II and AA is inhibited by N17Rac1 or MEK (mitogen-activated protein kinase/ERK kinase) inhibitor. These results demonstrate that Ang II stimulates ERK1/ ERK2 by AA and Nox4-derived reactive oxygen species, suggesting that these molecules act as downstream signal transducers of Ang II in the signalling pathway linking the Ang II receptor AT, to ERK1/ERK2 activation. This pathway involving AA, Rac1, Nox4, reactive oxygen species and ERK1/ERK2 may play an important role in Ang II-induced mesangial cell hypertrophy.