Sublytic C5b-9 complexes induce proliferative changes of glomerular mesangial cells in rat Thy-1 nephritis through TRAF6-mediated PI3K-dependent Akt1 activation
Sublytic C5b-9 complexes induce proliferative changes of glomerular mesangial cells in rat Thy-1 nephritis through TRAF6-mediated PI3K-dependent Akt1 activation
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Sublytic C5b-9 复合物通过 TRAF6 介导的 PI3K 依赖性 Akt1 激活诱导大鼠 Thy-1 肾炎肾小球系膜细胞的增殖变化
DOI：
10.1002/path.3011
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发表时间：
2012-03-01
影响因子：
7.3
通讯作者：
Wang, Yingwei
中科院分区：
文献类型：
--
作者：
Qiu, Wen;Zhang, Yan;Wang, Yingwei
类似于人类系膜增生性肾炎(MsPGN)的Thy-1肾炎(Thy-1N)大鼠肾小球系膜细胞(GMC)的增殖和细胞外基质(ECM)的分泌已被研究多年，但其机制，特别是C5b-9亚溶解复合体在THY-1N大鼠肾小球系膜细胞(GMC)激活及其调控中的作用尚不清楚。本研究检测了亚溶血C5b-9诱导的大鼠肾小球系膜细胞(体外)和Thy-1N大鼠肾组织中GMCs的增殖和ECM的产生，以及PI3K/Akt的作用和调节。结果表明，无论是体内外，GMCs的增殖和ECM的分泌都显著增加，PI3K/Akt1的激活和调节，如肿瘤坏死因子受体相关因子6(TRAF6)介导的Akt1泛素化和PI3K依赖的Akt1磷酸化，参与了Thy-1N诱导的GMCs增殖和ECM分泌。另一方面，沉默TRAF6、PI3K或Akt1基因可明显减轻Thy-1N大鼠的增殖损伤和尿蛋白分泌。以上结果提示，Thy-1N大鼠肾小球系膜细胞C5b-9复合体可通过TRAF6介导的PI3K依赖的Akt1活化促进GMCs增殖和细胞外基质的产生，其中Akt1信号分子的泛素化和磷酸化在Thy-1N大鼠肾小球系膜细胞增殖改变的发生和发展中起重要作用。版权所有(C)2012年大不列颠和爱尔兰病理学会。作者：John Wiley&Sons，Ltd.
The proliferation of glomerular mesangial cells (GMCs) and secretion of extracellular matrix (ECM) in rat Thy-1 nephritis (Thy-1N), resembling human mesangioproliferative glomerulonephritis (MsPGN), have been studied for many years, but the mechanisms, especially the role of signalling pathway activation and its regulation in GMCs triggered by sublytic C5b-9 complexes in Thy-1N rats remain largely unclear. In the study, the proliferation of GMCs and production of ECM as well as the role of PI3K/Akt and its regulation, both in GMCs induced by sublytic C5b-9 (in vitro) and in the renal tissues of rats with Thy-1N (in vivo), were determined and the results revealed that GMCs proliferation and ECM secretion, both in vitro and in vivo, were notably increased, and that PI3K/Akt1 activation and its regulation, such as TNF receptor-associated factor 6 (TRAF6)-mediated Akt1 ubiquitination and PI3K-dependent Akt1 phosphorylation, were involved in the process of Thy-1N induction. On the other hand, silence of the TRAF6, PI3K or Akt1 genes could obviously diminish the proliferative damages and urinary protein secretion of Thy-1N rats. Together, these data implicated that sublytic C5b-9 complexes in Thy-1N rats could promote GMCs proliferation and ECM production through TRAF6-mediated PI3K-dependent Akt1 activation, in which the ubiquitination and phosphorylation of the Akt1 signal molecule played an important role in the initiation and development of the proliferative changes in the rats with Thy-1N. Copyright (C) 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.