Angiotensin II induces DNA damage via AT1 receptor and NADPH oxidase isoform Nox4
Angiotensin II induces DNA damage via AT1 receptor and NADPH oxidase isoform Nox4
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DOI：
10.1093/mutage/ges033
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发表时间：
2012-11-01
期刊：
影响因子：
2.7
通讯作者：
Schupp, Nicole
中科院分区：
文献类型：
--
作者：
Fazeli, Gholamreza;Stopper, Helga;Schupp, Nicole
流行病学研究表明，高血压患者的肾癌发病率和癌症死亡率较高。肾素血管紧张醛固酮系统的激活导致活性氧（ROS）的形成。在体外肾细胞和离体灌注小鼠肾脏中，我们可以显示血管紧张素 II (Ang II) 的 DNA 损伤潜力。在此，研究了 Ang II 遗传毒性所涉及的途径。在具有近端肾小管细胞特性的肾细胞系中，观察到 NADPH 氧化酶的激活和 ROS 的产生，导致 DNA 链断裂的形成和微核诱导。这种 DNA 损伤是由 Ang II 1 型受体 (AT1R) 和 G 蛋白 G(-q/11) 介导的。随后，磷脂酶 C (PLC) 被激活，细胞内钙增加。内质网的钙储存和细胞外的钙都参与了 Ang II 的遗传毒性。在下游，可以检测到蛋白激酶 C (PKC) 的作用，因为它的抑制作用阻碍了 Ang II 损害细胞。尽管 PKC 被激活，但通过小干扰 RNA 下调测试，未发现其已知靶标（包含 Nox2 亚基的 NADPH 氧化酶亚型）的参与。负责 Ang II 的 DNA 损伤活性的是含有 Nox4 亚基的 NADPH 氧化酶同工型。总之，在肾细胞中，Ang II 的 DNA 损伤活性取决于 AT1R 通过 PLC、PKC 和钙信号传导介导的 NADPH 氧化酶激活，其中 NADPH 亚基 Nox4 发挥着至关重要的作用。
Epidemiological studies revealed increased renal cancer incidences and higher cancer mortalities in hypertensive individuals. Activation of the reninangiotensinaldosterone system leads to the formation of reactive oxygen species (ROS). In vitro, in renal cells, and ex vivo, in the isolated perfused mouse kidney, we could show DNA-damaging potential of angiotensin II (Ang II). Here, the pathway involved in the genotoxicity of Ang II was investigated. In kidney cell lines with properties of proximal tubulus cells, an activation of NADPH oxidase and the production of ROS, resulting in the formation of DNA strand breaks and micronuclei induction, was observed. This DNA damage was mediated by the Ang II type 1 receptor (AT1R), together with the G protein G(-q/11). Subsequently, phospholipase C (PLC) was activated and intracellular calcium increased. Both calcium stores of the endoplasmic reticulum and extracellular calcium were involved in the genotoxicity of Ang II. Downstream, a role for protein kinase C (PKC) could be detected, because its inhibition hindered Ang II from damaging the cells. Although PKC was activated, no involvement of its known target, the NADPH oxidase isoform containing the Nox2 subunit, could be found, as tested by small-interfering RNA down-regulation. Responsible for the DNA-damaging activity of Ang II was the NADPH oxidase isoform containing the Nox4 subunit. In summary, in kidney cells the DNA-damaging activity of Ang II depends on an AT1R-mediated activation of NADPH oxidase via PLC, PKC and calcium signalling, with the NADPH subunit Nox4 playing a crucial role.