DNA induction of MDM2 promotes proliferation of human renal mesangial cells and alters peripheral B cells subsets in pediatric systemic lupus erythematosus
DNA induction of MDM2 promotes proliferation of human renal mesangial cells and alters peripheral B cells subsets in pediatric systemic lupus erythematosus
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MDM2 的 DNA 诱导促进人肾系膜细胞增殖并改变儿童系统性红斑狼疮的外周 B 细胞亚群
DOI：
10.1016/j.molimm.2018.01.003
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发表时间：
2018-02
影响因子：
3.6
通讯作者：
Tongxin Chen
中科院分区：
文献类型：
--
作者：
Chenxing Zhang;Ji Chen;Li Cai;Jing Wu;Jiayuan Wang;Lanfang Cao;Wei Zhou;Tongxin Chen
本研究旨在探讨MDM 2在儿童系统性红斑狼疮（pSLE）狼疮性肾炎（LN）发病机制中的作用。通过免疫印迹和免疫荧光染色证实，MDM2在SLE患者外周血单个核细胞（PBMCs）和肾组织中的表达均高于对照组。采用流式细胞术检测SLE患者和健康对照组（HC）外周血中CD4+T、CD8+T和B细胞凋亡和坏死的百分率，并检测血浆游离DNA（cfDNA）水平。我们还证实了凋亡和坏死的CD4+T细胞的升高是pSLE中cfDNA血浆水平升高的主要原因。细胞增殖实验和细胞周期分析显示，转染DNA后，人肾小球系膜细胞（HRMC）中MDM2增加，P53和P21减少，细胞增殖率和S期细胞比例增加。然而，MDM2抑制逆转了这一趋势。阻断MDM2后，记忆转换B细胞比例降低，双阴性B细胞比例增加。总之，我们的研究提供了第一个证据表明，DNA诱导的MDM 2促进HRMC的增殖和改变外周B细胞亚群在pSLE。因此，我们的研究不仅阐明了MDM2在儿童LN中的发病机制，而且为药物开发提供了新的靶点。综上所述，我们的数据表明，细胞凋亡，cfDNA和MDM2可以形成一个病理轴在SLE，特别是在pSLE。
The study is aimed to investigate the role of MDM2 in the pathogenesis of lupus nephritis (LN) in pediatric SLE (pSLE). We confirmed that MDM2 expression was increased in peripheral blood mononuclear cells (PBMCs) as well as renal specimen of SLE compared with that of controls by western blot and immunofluorescence staining. Percentage of apoptotic and necrotic CD4+T, CD8+T and B cells were detected by flow cytometry respectively and levels of plasma cell free DNA (cfDNA) were quantified in SLE and healthy controls (HC). We also proved that elevated apoptotic and necrotic CD4+T cells were the main cause for increased plasma levels of cfDNA in pSLE. Additionally, upon DNA transfection MDM2 increased while P53 and P21 decreased in human renal mesangial cells (HRMC), with concomitant increase in proliferation rate and proportion of cells in S phase, as demonstrated by cell proliferation assay and cell cycle analysis. However, MDM2 inhibition reversed the trend. Furthermore, percentage of switched memory B cells decreased and proportion of double negative B cells increased upon blockage of MDM2 in PBMC. In summary, our study provided the first evidence that DNA induction of MDM2 promotes proliferation of HRMC and alters peripheral B cells subsets in pSLE. Thus our study has not only elucidated the pathogenesis of MDM2 in pediatric LN but also provided a novel target for drug development. In conclusion, our data suggested that apoptosis, cfDNA and MDM2 could form a pathological axis in SLE, especially in pSLE.
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影响因子：
7.3
作者：
Darrah E;Andrade F
通讯作者：
Andrade F
影响因子：
3
作者：
Kumar D;Bhaskaran M;Alagappan L;Tori D;Yadav I;Konkimalla S;Magoon S;Singhal PC
通讯作者：
Singhal PC
影响因子：
3.4
作者：
Atef Elmougy;A. Sarhan;A. Hammad;A. El-refaey;M. Zedan;R. Eid;Wafaa Limon;A. A. Elrahman-A.;Fatma Elhussieni;Enas El-Sherbeny;A. Bakr
通讯作者：
Atef Elmougy;A. Sarhan;A. Hammad;A. El-refaey;M. Zedan;R. Eid;Wafaa Limon;A. A. Elrahman-A.;Fatma Elhussieni;Enas El-Sherbeny;A. Bakr
影响因子：
5.1
作者：
Hao Zhao;Ruijuan Shen;Xiao-bin Dong;Yi Shen
通讯作者：
Hao Zhao;Ruijuan Shen;Xiao-bin Dong;Yi Shen
影响因子：
3.7
作者：
gren, J.;Thiemermann, C.;Aasen, A. O.
通讯作者：
Aasen, A. O.