Transglutaminase-1 protects renal epithelial cells from hydrogen peroxide-induced apoptosis through activation of STAT3 and AKT signaling pathways
Transglutaminase-1 protects renal epithelial cells from hydrogen peroxide-induced apoptosis through activation of STAT3 and AKT signaling pathways
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DOI：
10.1152/ajprenal.00251.2009
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发表时间：
2009-11-01
影响因子：
4.2
通讯作者：
Zhuang, Shougang
中科院分区：
文献类型：
--
作者：
Ponnusamy, Murugavel;Pang, Maoyin;Zhuang, Shougang
张忠，龚锐，陈叶，庄思。转谷氨酰胺酶-1通过激活STAT3和AKT信号通路保护过氧化氢诱导的肾上皮细胞凋亡。[J] .中国生物医学工程学报，2009,31(4):555 - 557。首次发表于2009年8月26日；doi: 10.1152 / ajprenal.00251.2009。我们最近的研究表明，转谷氨酰胺酶-1 （TGase-1）在小鼠肾近端小管细胞（RPTC）中唯一表达，并介导细胞增殖。在本研究中，我们研究了TGase-1在氧化损伤后RPTC细胞存活中的作用以及TGase-1调控的存活信号通路。暴露于过氧化氢（H2O2）导致RPTC细胞凋亡和TGase活性增加。在h2o2处理的RPTC中，用一种TGase抑制剂（MDC）抑制TGase活性或用小干扰（si） RNA敲低TGase-1可增强细胞凋亡并降低细胞存活率。相反，TGase-1的过表达使RPTC对H2O2毒性更具抗性，而MDC处理阻断了这种反应。在RPTC细胞凋亡的同时，观察到AKT、转录信号传导和激活因子-3 （STAT3）和葡萄糖原合成酶激酶-3 β (GSK-3 β)的磷酸化。用MDC或TGase-1 siRNA预处理细胞可抑制所有这些分子的磷酸化。抑制AKT或STAT3通路均可增强h2o2诱导的细胞死亡，并通过丝氨酸9的去磷酸化增加GSK-3 β活性。此外，GSK-3 β抑制剂可降低h2o2诱导的细胞凋亡，并消除AKT和STAT3抑制的促死亡作用。因此，我们已经确定TGase-1是肾上皮细胞中的一种新的存活因子，它通过激活氧化损伤后的AKT和STAT3信号通路来促进细胞存活。
Ponnusamy M, Pang M, Annamaraju PK, Zhang Z, Gong R, Chin YE, Zhuang S. Transglutaminase-1 protects renal epithelial cells from hydrogen peroxide-induced apoptosis through activation of STAT3 and AKT signaling pathways. Am J Physiol Renal Physiol 297: F1361-F1370, 2009. First published August 26, 2009; doi: 10.1152/ajprenal.00251.2009.-Our recent studies showed that transglutaminase-1 (TGase-1) is uniquely expressed in mouse renal proximal tubular cells (RPTC) and mediates cell proliferation. In this study, we investigated the role of TGase-1 in cell survival and the survival signaling pathways regulated by TGase-1 in RPTC following oxidant injury. Exposure of RPTC to hydrogen peroxide (H2O2) resulted in apoptosis and an increase in TGase activity. Inhibition of TGase activity with monodansylcadervine (MDC), a TGase inhibitor, or knockdown of TGase-1 with small interference (si) RNA enhanced apoptosis and decreased cell survival in H2O2-treated RPTC. Conversely, overexpression of TGase-1 rendered RPTC more resistant to H2O2 toxicity and MDC treatment blocked this response. Concurrent with RPTC apoptosis, phosphorylation of AKT, signal transducer and activator of transcription-3 (STAT3), and glucogen synthase kinase-3 beta (GSK-3 beta) were observed. Pretreatment of cells with MDC or TGase-1 siRNA inhibited phosphorylation of all these molecules. Inhibition of either the AKT or STAT3 pathway potentiated H2O2-induced cell death and increased GSK-3 beta activity by dephosphorylation at serine 9. Furthermore, treatment with GSK-3 beta inhibitors reduced H2O2-induced apoptosis and abolished the death-promoting effect of AKT and STAT3 inhibition. Therefore, we have identified TGase-1 as a novel survival factor in renal epithelial cells and it contributes to cell survival through activation of the AKT and STAT3 signaling pathways following oxidant injury.