Venkatesan Balachandar, Mahimainathan Lenin, Das Falguni, Ghosh-Choudhury Nandini, Ghosh Choudhury Goutam
Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
J Cell Physiol. 2007 May;211(2):457-67. doi: 10.1002/jcp.20953.
Reactive oxygen species (ROS) contribute to many glomerular diseases by targeting mesangial cells. ROS have been shown to regulate expression of many antioxidant enzymes including catalase. The mechanism by which the expression of catalase protein is regulated by ROS is not precisely known. Here we report that increased intracellular ROS level by hydrogen peroxide (H(2)O(2)) reduced the expression of catalase. H(2)O(2) increased phosphorylation of Akt kinase in a dose-dependent and sustained manner with a concomitant increase in the phosphorylation of FoxO1 transcription factor. Further analysis revealed that H(2)O(2) promoted rapid activation of phosphatidylinositol (PI) 3 kinase. The PI 3 kinase inhibitor Ly294002 and expression of tumor suppressor protein PTEN inhibited Akt kinase activity, resulting in the attenuation of FoxO1 phosphorylation and preventing the downregulating effect of H(2)O(2) on catalase protein level. Dominant negative Akt attenuated the inhibitory effect of H(2)O(2) on expression of catalase. Constitutively active FoxO1 increased the expression of catalase. However, dominant negative FoxO1 inhibited catalase protein level. Catalase transcription was reduced by H(2)O(2) treatment. Furthermore, expression of dominant negative Akt and constitutively active FoxO1 increased catalase transcription, respectively. These results demonstrate that ROS downregulate the expression of catalase in mesangial cells by PI 3 kinase/Akt signaling via FoxO1 as a target.
活性氧（ROS）通过作用于系膜细胞导致多种肾小球疾病。已表明ROS可调节包括过氧化氢酶在内的多种抗氧化酶的表达。过氧化氢酶蛋白表达受ROS调节的机制尚不完全清楚。在此我们报告，过氧化氢（H₂O₂）使细胞内ROS水平升高会降低过氧化氢酶的表达。H₂O₂以剂量依赖性和持续性方式增加Akt激酶的磷酸化，同时FoxO1转录因子的磷酸化也增加。进一步分析显示，H₂O₂促进磷脂酰肌醇（PI）3激酶的快速激活。PI 3激酶抑制剂Ly294002以及肿瘤抑制蛋白PTEN的表达抑制了Akt激酶活性，导致FoxO1磷酸化减弱，并阻止了H₂O₂对过氧化氢酶蛋白水平的下调作用。显性负性Akt减弱了H₂O₂对过氧化氢酶表达的抑制作用。组成型活性FoxO1增加了过氧化氢酶的表达。然而，显性负性FoxO1抑制了过氧化氢酶蛋白水平。H₂O₂处理降低了过氧化氢酶的转录。此外，显性负性Akt和组成型活性FoxO1的表达分别增加了过氧化氢酶的转录。这些结果表明，ROS通过PI 3激酶/Akt信号传导，以FoxO1为靶点下调系膜细胞中过氧化氢酶的表达。
